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1. APOL1 polymorphisms and development of CKD in an identical twin donor and recipient pair. : Kidney donation in twins with APOL1 variant

Author: Kofman, Tomek, Audard, Vincent, Narjoz, Céline, Gribouval, Olivier, Matignon, Marie, Leibler, Claire, Desvaux, Dominique, Lang, Philippe, Grimbert, Philippe, Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: MESH : Polymorphism, Genetic, MESH : Male, MESH: Renal Insufficiency, Chronic, MESH : Young Adult, APOL1 polymorphism, kidney transplantation, MESH : Genotype, MESH : Renal Insufficiency, Chronic, MESH: Lipoproteins, HDL, MESH : Diseases in Twins, MESH: Kidney Transplantation, MESH: Genotype, MESH: Biopsy, MESH: Apolipoproteins, MESH: Polymorphism, Genetic, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, donor, MESH: Living Donors, MESH: Humans, urogenital system, MESH : Humans, MESH: Genetic Predisposition to Disease, MESH : Follow-Up Studies, MESH: Follow-Up Studies, MESH: Kidney, MESH: Male, MESH : Kidney, MESH : Twins, Monozygotic, MESH: Young Adult, MESH : Biopsy, MESH : Living Donors, outcome, MESH : Lipoproteins, HDL, MESH : Kidney Transplantation, MESH : Genetic Predisposition to Disease, MESH: Twins, Monozygotic, MESH: Diseases in Twins, MESH : Apolipoproteins
Abstract: International audience; We report an occurrence of progressive loss of transplant function and ultimately transplant failure after living related kidney transplantation involving monozygotic twin brothers of Afro-Caribbean origin who were both heterozygous for the G1 and G2 kidney disease risk alleles in the APOL1 gene, which encodes apolipoprotein L-I. A 21-year-old man with end-stage kidney disease of unknown cause received a kidney from his brother, who was confirmed as a monozygotic twin by microsatellite analysis. Thirty months after transplantation, the patient presented with proteinuria and decreased estimated glomerular filtration rate; a biopsy of the transplant showed typical focal segmental glomerulosclerosis lesions. He received steroid therapy, but progressed to kidney failure 5 years later. The twin brother had normal kidney function without proteinuria at the time of transplantation; however, 7 years later, he was found to have decreased estimated glomerular filtration rate (40mL/min/1.73m(2)) and proteinuria (protein excretion of 2.5g/d). APOL1 genotyping revealed that both donor and recipient were heterozygous for the G1 and G2 alleles. This case is in stark contrast to the expected course of kidney transplantation in identical twins and suggests a role for APOL1 polymorphisms in both the donor and recipient.
Published: 2014
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2. Allo-Immune Membranous Nephropathy and Recombinant Aryl Sulfatase Replacement Therapy: A Need for Tolerance Induction Therapy

Author: Laure-Hélène Noël, Vassili Valayannopoulos, Pierre Ronco, Niaudet P, Olivia Boyer, Patrice Callard, Pascale de Lonlay, Hanna Debiec, Hélène Sarda, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence pour les maladies métaboliques héréditaires [CHU Necker Enfants Malades - AP-HP], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pédiatrie [CH René Dubos, Pontoise], Centre Hospitalier René Dubos [Pontoise], Research is supported by European Research Council Grant ERC-2012-ADG_20120314 (Grant Agreement 322947), Agence Nationale pour la Recherche Programme Blanc SVSE1 (2012) Decision ANR-12-BSE1-0002-01, Fondation pour la Recherche Médicale Equipe FRM 2012 grant, and 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases)., European Project: 322947,EC:FP7:ERC,ERC-2012-ADG_20120314,OSAI(2013), European Project: 305608,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EURENOMICS(2012), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie pathologique [CHU Necker], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie, Hopital Réné Dubos-CH Pontoise, European Research Council Grant ERC-2012-ADG_20120314 (Grant Agreement 322947), Agence Nationale pour la Recherche Programme Blanc SVSE1 (2012) Decision ANR-12-BSE1-0002-01, Fondation pour la Recherche Médicale Equipe FRM 2012 grant, and 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare KidneyDiseases)., Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [CHU Tenon], RONCO, Pierre, Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI) - OSAI - - EC:FP7:ERC2013-05-01 - 2018-04-30 - 322947 - VALID, European Consortium for High-Throughput Research in Rare Kidney Diseases - EURENOMICS - - EC:FP7:HEALTH2012-10-01 - 2017-09-30 - 305608 - VALID, Service de Département de Néphrologie = Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service de néphrologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, N-Acetylgalactosamine-4-Sulfatase, Mucopolysaccharidosis type VI, MESH: Glomerulonephritis, Membranous, MESH : Child, Preschool, MESH : N-Acetylgalactosamine-4-Sulfatase, Gastroenterology, Glomerulonephritis, Membranous, MESH: Recombinant Proteins, 0302 clinical medicine, Isoantibodies, Medicine, MESH : Glomerulonephritis, Membranous, MESH: Enzyme Replacement Therapy, 0303 health sciences, Proteinuria, Mucopolysaccharidosis VI, MESH : Enzyme Replacement Therapy, MESH : Immune Tolerance, Glomerulonephritis, General Medicine, Enzyme replacement therapy, Recombinant Proteins, 3. Good health, Tolerance induction, Nephrology, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine.symptom, Brief Communications, medicine.medical_specialty, MESH: Immune Tolerance, MESH: Mucopolysaccharidosis VI, MESH : Recombinant Proteins, MESH : Male, MESH : Isoantibodies, MESH: N-Acetylgalactosamine-4-Sulfatase, Nephropathy, 03 medical and health sciences, Membranous nephropathy, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Immune Tolerance, Humans, Enzyme Replacement Therapy, 030304 developmental biology, MESH: Humans, business.industry, MESH : Humans, MESH: Child, Preschool, medicine.disease, MESH: Isoantibodies, MESH: Male, MESH : Mucopolysaccharidosis VI, Immunology, business, Nephrotic syndrome, 030217 neurology & neurosurgery
Abstract: International audience; Nephrotic syndrome was reported in a highly-sensitized patient receiving enzyme replacement therapy (ERT) for Pompe disease, but the prevalence of ERT-induced renal complications and mechanisms to facilitate readministration of ERT in these patients remain unexplored. This work identifies a new antigen responsible for secondary membranous nephropathy (MN) in a patient with mucopolysaccharidosis type VI caused by aryl sulfatase B (ASB) deficiency. ERT (recombinant human ASB [rhASB]; 1 mg/kg per week) started at the age of 4 years led to a high anti-rhASB titer and dramatically improved clinical manifestations. However, 16 months later, the patient suddenly developed nephrotic syndrome resistant to steroid therapy 1 week after orthopedic surgery. Examination of the kidney biopsy specimen revealed glomerular deposition of IgG (mostly IgG4, C3, and C5b-9) in a granular pattern typical of MN. Double immunofluorescence staining showed that subepithelial granular deposits contained rhASB colocalized with IgG. Ig eluted from the patient's biopsy specimen reacted specifically with rhASB. On discontinuation of ERT, proteinuria progressively decreased, but the patient's clinical condition markedly deteriorated. Induction of tolerance to rhASB was initiated by coadministration of low-dose corticosteroids, rituximab, intravenous Igs, and oral methotrexate. ERT was resumed 8 weeks after starting immunosuppressive therapy without inducing a rebound of antibody titer or an increase in proteinuria. We conclude that the allo-immune response to the recombinant rhASB caused the nephropathy. Considering the critical requirement for ERT in patients with such enzyme deficiencies, immune tolerance induction should be advocated in the patients with allo-immune MN.
Published: 2014
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3. The kidney as a reservoir for HIV-1 after renal transplantation

Author: Andrea Onetti Muda, Marie-Claire Gubler, Mordi Muorah, Guillaume Canaud, Frank Bienaimé, Corinne Antignac, Christine Rouzioux, Louise Galmiche, Jean-Paul Viard, Olivier Gribouval, Dany Anglicheau, Fabiola Terzi, Laure-Hélène Noël, Marc-Olivier Timsit, Gérard Friedlander, Anne Scemla, Christophe Legendre, Véronique Avettand-Fenoel, Frank Martinez, Anne-Pascale Satie, Rebecca Sberro-Soussan, Nathalie Dejucq-Rainsford, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Université Paris Descartes - Paris 5 (UPD5), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de Virologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Université Paris Descartes - Paris 5 ( UPD5 ), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CHRU Brest - Service de Rhumatologie ( CHU - BREST - Rhumato ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Pathology, medicine.medical_specialty, education.field_of_study, Kidney, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Population, General Medicine, Hepatitis C, Biology, medicine.disease, 3. Good health, Podocyte, Transplantation, medicine.anatomical_structure, surgical procedures, operative, Nephrology, Immunology, medicine, education, Viral load, Kidney transplantation, Subclinical infection
Abstract: International audience; Since the recent publication of data showing favorable outcomes for patients with HIV-1 and ESRD, kidney transplantation has become a therapeutic option in this population. However, reports have documented unexplained reduced allograft survival in these patients. We hypothesized that the unrecognized infection of the transplanted kidney by HIV-1 can compromise long-term allograft function. Using electron microscopy and molecular biology, we examined protocol renal transplant biopsies from 19 recipients with HIV-1 who did not have detectable levels of plasma HIV-1 RNA at transplantation. We found that HIV-1 infected the kidney allograft in 68% of these patients. Notably, HIV-1 infection was detected in either podocytes predominately (38% of recipients) or tubular cells only (62% of recipients). Podocyte infection associated with podocyte apoptosis and loss of differentiation markers as well as a faster decline in allograft function compared with tubular cell infection. In allografts with tubular cell infection, epithelial cells of the proximal convoluted tubules frequently contained abnormal mitochondria, and both patients who developed features of subclinical acute cellular rejection had allografts with tubular cell infection. Finally, we provide a novel noninvasive test for determining HIV-1 infection of the kidney allograft by measuring HIV-1 DNA and RNA levels in patients' urine. In conclusion, HIV-1 can infect kidney allografts after transplantation despite undetectable viremia, and this infection might influence graft outcome.
Published: 2014
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4. Mainzer-Saldino syndrome is a ciliopathy caused by mutations in the IFT140 gene

Author: Nora Shannon, M. Le Merrer, Heleen H. Arts, Emilie Filhol, Isabelle Perrault, Machteld M. Oud, Albane A. Bizet, Sylvain Hanein, Arnold Munnich, Véronique Baudouin, Jean-Claude Kaplan, Corinne Antignac, F Collins, V. Cormier Daire, PL Beales, Sophie Saunier, Mustafa A. Salih, Eduardo Silva, Christine Pietrement, Jean-Michel Rozet, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Clinical Genetics, Westmead Hospital [Sydney], Division of Pediatric Neurology, King Khalid University Hospital, Department of Ophthalmology, Universidade de Coimbra [Coimbra], Service de Néphrologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Human Genetics, Radboud University Medical Center [Nijmegen]-Faculty of Medical Sciences, Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, Service de Pédiatrie, Centre Hospitalier Universitaire de Reims (CHU Reims)-American Memorial Hospital (Reims), Molecular Medicine Unit, University College of London [London] (UCL)-Institute of Child Health, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Westmead Hospital, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Centre Hospitalier Universitaire de Reims ( CHU Reims ) -American Memorial Hospital (Reims), University College of London [London] ( UCL ) -Institute of Child Health, and BMC, Ed.
Subjects: Bone development, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 01 natural sciences, Ciliopathies, 03 medical and health sciences, Intraflagellar transport, MAINZER-SALDINO SYNDROME, 0103 physical sciences, medicine, lcsh:QH573-671, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, 010304 chemical physics, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, lcsh:Cytology, Cilium, Cell Biology, medicine.disease, Human genetics, Ciliopathy, Oral Presentation, sense organs
Abstract: Ciliopathies is an emerging class of genetic disorders due to altered cilia assembly, maintenance or function. Syndromic ciliopathies affecting bone development have been classified as skeletal ciliopathies. Mutations in genes encoding components of the intraflagellar transport (IFT) complex A, that drives retrograde ciliary transport, are a major cause of skeletal ciliopathies. Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure and early-onset severe retinal dystrophy.
Published: 2012

5. Alteration of nephrocystins and IFT-A proteins causes similar ciliary phenotypes leading to Nephronophthisis

Author: Flora Silbermann, Corinne Antignac, Anthony Henneveu, Isabelle Perrault, Emilie Montenont, Alexandre Benmerah, Sophie Saunier, Christine Boyle-Feysot, Philippe Bastin, Emilie Filhol, Albane A. Bizet, Heleen H. Arts, Jean-Michel Rozet, Thierry Blisnick, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie Cellulaire des Trypanosomes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Nijmegen Medical Center, Radboud University [Nijmegen], BMC, Ed., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Radboud university [Nijmegen], Néphropathies héréditaires et rein en développement ( UMR_S 983 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Genetics, Axoneme, Candidate gene, lcsh:Cytology, Cilium, Wnt signaling pathway, Cell Biology, Biology, medicine.disease, Phenotype, Cell biology, Ciliopathy, Intraflagellar transport, Nephronophthisis, Poster Presentation, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, sense organs, lcsh:QH573-671, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract: International audience; Nephronophtisis (NPH) is a kidney ciliopathy often associated with extra-renal defects and for which 12 genes (NPHP1-12) have been identified. NPHP1 and NPHP4 control the ciliary access at the transition zone and the velocity of some intraflagellar transport (IFT)/BBS proteins in C.elegans. Recently, in a collaborative effort, we have identified, in families with isolated NPH, mutations in TTC21B as well as in WDR19, which encode the retrograde IFT-A proteins IFT139 and IFT144, respectively. By ciliome sequencing of 1600 candidate genes from 14 NPH patients followed by Sanger sequencing of a cohort of 52 patients, we have found respectively 8 and 7 patients carrying pathogenic missense mutations in genes coding IFT-A proteins, including WDR35, TTC21B and IFT140, which could partially affect their function. Together, these results indicate that IFT-A are involved in nephronophtisis. Moreover, alteration of cilia length was observed in patient kidney, Nphp4-/- mice kidney tubules and NPHP1 or NPHP4 knockdown IMCD3 cell lines. In these cells, primary cilia present swellings at the distal region accompanied by an accumulation of IFT-B at the base and the tip, similar to what was observed in IFT-A mutants, suggesting a possible alteration of retrograde transport. Additionally, ARL13B, a small GTPase required for proper cilium shape and IFT stability, is absent along the axoneme of NPHP4-KD-IMCD cells. By controlling the entry of ciliary components at the transition zone, NPHP1 and NPHP4 may modulate IFT-A cargos thus participating in the same pathway (i.e. Wnt/PCP), alteration of which would lead to renal lesions observed in nephronophthisis.
Published: 2012
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6. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy

Author: Christophe Charasse, Miguel A. Alonso, Rodrick Montjean, Dominique Pouthier, Leila Balafrej, Pierre Ronco, Jacques Dantal, Georges Deschênes, Jean-Michel Vallat, Eric LeGuern, Guillaume Canaud, Alain Bonnardeaux, Anne Guiochon-Mantel, Marie-Josèphe Tête, Olivier Gribouval, Olivia Boyer, Laurence Richard, Christelle Arrondel, Philippe Petiot, Geneviève Benoit, Odile Dubourg, Alexandre Karras, Evelyne Huynh Cong, Isabelle Broutin, Emmanuelle Plaisier, Corinne Antignac, Géraldine Mollet, Claire Pouteil-Noble, Marie-Claire Gubler, Sophie Saunier, Benoît Funalot, Patrice Deteix, Fabien Nevo, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Biochimie et Génétique Moléculaire [CHU Limoges], CHU Limoges, Centre de référence national neuropathies périphériques rares [CHU Limoges], Service de Neurologie [CHU Limoges], Service de néphrologie pédiatrique, Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], SARS International Centre for Marine Molecular Biology, Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Avenir Tour Lavoisier, Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Service de néphrologie et transplantation, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche Guy- Bernier, Hôpital Maisonneuve-Rosemont, Service de transplantation et soins intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], CH de Saint-Brieuc, Service de Néphrologie et Immunologie Clinique, Hôtel Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Paris Diderot - Paris 7 (UPD7), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de neurologie, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Service de Néphrologie, Centre Hospitalier de Luxembourg [Luxembourg] (CHL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5), Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Service de Génétique Médicale [CHU Necker], Néphropathies héréditaires et rein en développement ( UMR_S 983 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Descartes - Paris 5 ( UPD5 ), Service de néphrologie et dialyses, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université de Montréal-CHU Sainte Justine [Montréal], Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Hôtel Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Université Paris Diderot - Paris 7 ( UPD7 ), CHU Gabriel Montpied ( CHU ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hospices Civils de Lyon ( HCL ) -Hôpital de la Croix-Rousse [CHU - HCL], Centre Hospitalier de Luxembourg, Centre de Référence pour les Epilepsies Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Centre de Référence pour les Epilepsies Rares, Service de Génétique [Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centro de Biología Molecular Severo Ochoa ( CBMSO ), Universidad Autonoma de Madrid ( UAM ) -Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ), RONCO, Pierre, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), CHU de Saint-Brieuc, Agence Nationale de la Recherche (France), Association Française contre les Myopathies, Fondation pour la Recherche Médicale, Fonds de la Recherche en Sante du Québec, and Ministerio de Ciencia e Innovación (España)
Subjects: Male, Charcot–Marie–Tooth neuropathy, Pathology, MESH : Actins, MESH : Charcot-Marie-Tooth Disease, urologic and male genital diseases, Mice, Myelin, 0302 clinical medicine, MESH : Child, Charcot-Marie-Tooth Disease, MESH: Child, MESH: Charcot-Marie-Tooth Disease, Medicine, MESH: Animals, Age of Onset, Child, 0303 health sciences, MESH: Middle Aged, Glomerulosclerosis, Focal Segmental, General Medicine, female genital diseases and pregnancy complications, MESH : Age of Onset, 3. Good health, MESH : Phenotype, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Myelin maintenance, MESH: Young Adult, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Myelin and Lymphocyte-Associated Proteolipid Proteins, MESH: Proteolipids, MESH : Heterozygote, medicine.medical_specialty, Proteolipids, MESH: Age of Onset, MESH : Young Adult, Formins, MESH: Phenotype, MESH: Actins, 03 medical and health sciences, MESH : Adolescent, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, MESH: Myelin Proteins, MESH : Middle Aged, MESH: Adolescent, MESH: Humans, MESH : Humans, Membrane Transport Proteins, Kidney metabolism, MESH: Adult, medicine.disease, MESH : Glomerulosclerosis, Focal Segmental, INF2, Endocrinology, Mutation, MESH: Schwann Cells, MESH: Female, 030217 neurology & neurosurgery, Kidney, MESH: Membrane Transport Proteins, Glomerulosclerosis, Focal segmental glomerulosclerosis, MESH : Membrane Transport Proteins, Peripheral myelin protein 22, MESH : Myelin and Lymphocyte-Associated Proteolipid Proteins, MESH : Female, MESH: Heterozygote, Myelin and Lymphocyte-Associated Proteolipid Proteins, Microfilament Proteins, Middle Aged, MESH : Adult, MESH : Kidney, Phenotype, medicine.anatomical_structure, Female, MESH : Mutation, Myelin Proteins, Adult, Heterozygote, MESH: Mutation, Adolescent, MESH : Microfilament Proteins, MESH: Glomerulosclerosis, Focal Segmental, MESH : Male, MESH : Schwann Cells, MESH : Myelin Proteins, Young Adult, MESH: Microfilament Proteins, Glomerulopathy, Internal medicine, MESH : Mice, Animals, MESH: Mice, 030304 developmental biology, urogenital system, business.industry, Myelin protein zero, MESH: Kidney, Actins, MESH: Male, MESH : Proteolipids, Schwann Cells, MESH : Animals, business
Abstract: Backgrounds: Charcot–Marie–Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. We therefore hypothesized that INF2 may be responsible for cases of Charcot–Marie–Tooth neuropathy associated with FSGS., Methods: We performed direct genotyping of INF2 in 16 index patients with Charcot–Marie–Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. Histologic and functional studies were also conducted., Methods: We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Patients presented with an intermediate form of Charcot–Marie–Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2–MAL–CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42., Conclusions: INF2 mutations appear to cause many cases of FSGS-associated Charcot–Marie–Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function., Funded by the Agence Nationale de la Recherche and others.Supported by grants from the Association pour l'Utilisation du Rein Artificiel (to Dr. Antignac), Association Française contre les Myopathies (ANR-08-GENOPAT-017-01, to Dr. Antignac), Agence Nationale de la Recherche (PodoNet project number ANR-07-E-RARE-011-01 in the ERA-Net Consortium [JTC2007], to Dr. Antignac, and ANR-06-MRAR-024-01, to Dr. Leguern), Fondation pour la Recherche Médicale (project number DMP 2010-11-20-386, to Dr. Antignac, and doctoral funding, to Dr. Boyer), Association des Malades du Syndrome Néphrotique (to Dr. Mollet), Fonds de la Recherche en Santé du Québec (Fellowship Training Award to Dr. Benoit), and Ministerio de Ciencia e Innovación (BFU2009-07886 and CONSOLIDER COAT CSD2009-00016, to Dr. Alonso).
Published: 2011
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7. RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects

Author: Cécile, Jeanpierre, Guillaume, Macé, Mélanie, Parisot, Vincent, Morinière, Audrey, Pawtowsky, Marion, Benabou, Jelena, Martinovic, Jeanne, Amiel, Tania, Attié-Bitach, Anne-Lise, Delezoide, Philippe, Loget, Patricia, Blanchet, Dominique, Gaillard, Marie, Gonzales, Wassila, Carpentier, Patrick, Nitschke, Frédéric, Tores, Laurence, Heidet, Corinne, Antignac, Rémi, Salomon, J, Tantau, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), CHU Necker - Enfants Malades [AP-HP], Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biologie du développement[Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Service de génétique et de foetopathologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de bioinformatique, Université Paris Descartes - Paris 5 (UPD5), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte ( MARHEA ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Université de Reims Champagne-Ardenne ( URCA ) -IFR53-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Peer, Hal, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université
Subjects: medicine.medical_specialty, endocrine system, congenital, hereditary, and neonatal diseases and abnormalities, DNA Copy Number Variations, endocrine system diseases, 030232 urology & nephrology, Multicystic dysplastic kidney, Kidney development, medicine.disease_cause, Kidney, Polymorphism, Single Nucleotide, Congenital Abnormalities, 03 medical and health sciences, Open Reading Frames, 0302 clinical medicine, Fetus, renal agenesis, evolutionary conserved non-coding regions, Internal medicine, Genetics, medicine, Glial cell line-derived neurotrophic factor, Humans, Glial Cell Line-Derived Neurotrophic Factor, Multiple endocrine neoplasia, Renal agenesis, Genetics (clinical), Alleles, 030304 developmental biology, CNVs, 0303 health sciences, Mutation, variants, biology, Proto-Oncogene Proteins c-ret, Gene Expression Regulation, Developmental, medicine.disease, 3. Good health, Endocrinology, medicine.anatomical_structure, biology.protein, renal hypodysplasia, Kidney Diseases, Kidney disease, Signal Transduction
Abstract: International audience; Background The RET/GDNF signalling pathway plays a crucial role during development of kidneys and enteric nervous system. In humans, RET activating mutations cause multiple endocrine neoplasia, whereas inactivating mutations are responsible for Hirschsprung disease. RET mutations have also been reported in fetuses with renal agenesis, based on analysis of a small series of samples. Objective and Methods To better characterize the involvement of RET and GDNF in kidney development defects, we studied a series of 105 fetuses with bilateral defects including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3'UTRs and RET intron 1 were analysed. Copy number variations (CNVs) at these loci were also investigated. Results We identified: (i) a low frequency (< 7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (ii) no GDNF mutation; (iii) similar allele frequencies in patients and controls for most SNP variants, except for RET intron 1 variant rs2506012 that was significantly more frequent in affected fetuses than in controls (6% vs. 2%, P=0.01); (iv) distribution of the few rare RET variants unidentified in controls into the various 5'-ECRs; (v) absence of CNVs. Conclusion These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects. Analysis of a larger series of patients will be necessary to validate the association of the RET intron 1 variant rs2506012 with renal development defects.
Published: 2011
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8. Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome

Author: Ilmay Bilge, Corinne Antignac, Zelal Z. Bircan, Marie-Claire Gubler, Marie-Alice Macher, Olivier Gribouval, Olivia Boyer, Lisa M. Guay-Woodford, Fabien Nevo, Geneviève Benoit, Robert R. Weiss, Chantal Loirat, Kenza Soulami, Constantinos J. Stefanidis, Audrey Pawtowski, Georges Deschênes, Michelle Hall, Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Department of Pediatrics, Istanbul Faculty of Medicine, Department of Pediatric Nephrology, Kocaeli University Hospital, AP-HP, Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris, Department of Genetics, UAB Center for Clinical and Translational Science, Birmingham, Department of Pediatric Nephrology, Hôpital Universitaire des Enfants - Reine Fabiola, Brussels, Service de Néphrologie Dialyse Transplantation, CHU Ibn Rochd, Casablanca, Department of Pediatric Nephrology, Department of Pediatric Nephrology, Maria Fareri Children's Hospital, Valhalla, New York, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie pédiatrique, Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Department of Pediatrics, Istanbul University, Kocaeli University Hospital, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Genetics, UAB Center for Clinical and Translational Science, Université libre de Bruxelles (ULB)-Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Service de Néphrologie Dialyse Transplantation, CHU Ibn Rochd [Casablanca], 'P. & A. Kyriakou' Children's Hospital, Maria Fareri Children's Hospital, Financial support for this work was provided by grants from the Programme Hospitalier de Recherche Clinique (PHRC) AOM02123 (to C.A), the Association pour l'utilisation du Rein Artificiel (AURA) (to C.A), PodoNet (Clinical, Genetic and Experimental Research into Hereditary Diseases of the Podocyte) - project of the 2007 E-RARE program (to CA) and Fonds de la Recherche en Santé Québec (FRSQ) (Fellowship training Award to G.B.)., CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), New York Medical College (NYMC), Gribouval, Olivier, Néphropathies héréditaires et rein en développement ( UMR_S 983 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], Université de Montréal-CHU Sainte Justine [Montréal], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), and Université Libre de Bruxelles [Bruxelles] ( ULB ) -Hôpital Universitaire des Enfants - Reine Fabiola
Subjects: Male, Candidate gene, Nephrotic Syndrome, DNA Mutational Analysis, MESH : Aged, 030232 urology & nephrology, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Child, Preschool, medicine.disease_cause, Compound heterozygosity, Cohort Studies, 0302 clinical medicine, Focal segmental glomerulosclerosis, MESH: Aged, 80 and over, Phosphoinositide Phospholipase C, MESH : Child, PLCE1, MESH: Child, Missense mutation, MESH : Female, Molecular genetics, MESH: DNA Mutational Analysis, Child, MESH: Cohort Studies, Genetics (clinical), Genetics, MESH: Aged, Aged, 80 and over, 0303 health sciences, Mutation, MESH: Statistics, Nonparametric, MESH : Phosphoinositide Phospholipase C, MESH: Middle Aged, Renal Medicine, Glomerulosclerosis, Focal Segmental, MESH: Genetic Predisposition to Disease, MESH : Infant, MESH : Adult, Middle Aged, MESH: Infant, 3. Good health, MESH : Phenotype, Phenotype, Child, Preschool, Screening, Female, Steroids, MESH : Mutation, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Glomerulosclerosis, Focal Segmental, MESH : Male, MESH : Nephrotic Syndrome, MESH : Cohort Studies, MESH : DNA Mutational Analysis, Biology, MESH: Phenotype, Statistics, Nonparametric, 03 medical and health sciences, MESH : Adolescent, medicine, MESH: Phosphoinositide Phospholipase C, Humans, MESH : Middle Aged, Genetic Predisposition to Disease, MESH : Aged, 80 and over, MESH : Statistics, Nonparametric, 030304 developmental biology, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Humans, MESH: Child, Preschool, Infant, MESH: Adult, medicine.disease, mutations, MESH: Male, MESH: Steroids, Steroid-resistant nephrotic syndrome, MESH : Glomerulosclerosis, Focal Segmental, MESH : Genetic Predisposition to Disease, MESH: Nephrotic Syndrome, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, MESH : Steroids
Abstract: International audience; BACKGROUND: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCepsilon1) have been recently described in patients with early onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. METHOD: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutational analysis was performed in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid resistant NS presenting at a median age of 23.0 months (range 0-373). RESULTS: Homozygous or compound heterozygous mutations were identified in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. CONCLUSION: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF,IQGAP1 and NPHS1) were not identified, it is speculated that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.
Published: 2010
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9. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Author: Marie-Josèphe Tête, Matthias Hansen, Florie Lammens, Tobias Schäfer, Albert Bensman, Alexandra Cambier, Tobias B. Huber, Christoph J. Mache, Elisa Kuhn, Christian Brix Folsted Andersen, Corinne Isnard-Bagnis, Tarunveer S. Ahluwalia, Günter Klaus, Mathilda Bedin, Fabienne Jabot-Hanin, Julien Hogan, Laure Villoing-Gaudé, Timo Wagner, Patrick Nitschke, Carole Tournant, Marcus R. Benz, Maik Grohmann, Markus Gödel, Aude Servais, Corinne Antignac, Cécile Vigneau, Ferielle Louillet, Christine Bole-Feysot, Véronique Baudouin, Iseline Bouteau, Lars Pape, Kay Latta, Carsten Bergmann, Yong Li, Vincent Morinière, Saoussen Krid, Olivier Gribouval, Olivia Boyer, Bruno Ranchin, Anna Köttgen, Matias Simons, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], School of Software (THSS), Tsinghua University [Beijing], Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Service de néphrologie et pédiatrie générale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de Néphrologie Rhumatologie Dermatologie, HCL Groupement Hospitalier Est-Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de référence Maladies Rénales Rares, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'urologie, néphrologie et transplantation [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Pediatric Kidney, Hannover Medical School [Hannover] (MHH)-Children's Hospital, Renal Division, University Medical Center Freiburg, Freiburg, Germany, Service de Génétique Médicale [CHU Necker], Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Plateforme de bioinformatique, Université Paris Descartes - Paris 5 (UPD5), IT University of Copenhagen, NNF18OC0052457, Novo Nordisk Fonden, KO 3598/5-1,KIDGEM SFB1140 246781735, Deutsche Forschungsgemeinschaft, ANR-10-IAHU-01,ANR-14-ACHN-0013, Agence Nationale de la Recherche, 01GM1515C, Federal Ministry or Education and Research, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Tsinghua University [Beijing] (THU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-HCL Groupement Hospitalier Est-Centre de référence Maladies Rénales Rares, Service d'Urologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), IT University of Copenhagen (ITU), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and ANR-14-ACHN-0013,NEPHROFLY,Utilisation de Drosophila melanogaster pour étudier les maladies génétiques du rein(2014)
Subjects: Male, 0301 basic medicine, Nephrology, medicine.medical_specialty, Anemia, Megaloblastic, [SDV]Life Sciences [q-bio], Renal function, Receptors, Cell Surface, Kidney, urologic and male genital diseases, Gastroenterology, Kidney Tubules, Proximal, 03 medical and health sciences, 0302 clinical medicine, Focal segmental glomerulosclerosis, Malabsorption Syndromes, Internal medicine, Chronic kidney disease, medicine, Genetics, Albuminuria, Humans, Alport syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, Proteinuria, business.industry, urogenital system, Vitamin B 12 Deficiency, General Medicine, medicine.disease, Cubilin, female genital diseases and pregnancy complications, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Female, Clinical Medicine, medicine.symptom, business, Nephrotic syndrome, Genetic diseases
Abstract: International audience; BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).
Published: 2020
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10. Cell type‐specific regulation of ciliary transition zone assembly in vertebrates

Author: Tristan Leu, Antonia Wiegering, Andreas Struchtrup, Sophie Saunier, André Spychala, Stefanie Dahmen, Stefanie Kuschel, Christoph Gerhardt, Flora Legendre, Ulrich Rüther, Renate Dildrop, Thomas Zobel, Lisa Kalfhues, Sylvie Schneider-Maunoury, Johanna Maria Lier, Christine Vesque, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie du Développement [IBPS] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Saunier, Sophie
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Medizin, Cell Cycle Proteins, Ciliopathies, Ciliary transition zone assembly, Mice, Rpgrip1l, 0302 clinical medicine, Cells, Cultured, Caenorhabditis elegans, Mice, Knockout, General Neuroscience, Cilium, Nuclear Proteins, Vertebrate, Articles, Cell biology, [SDV] Life Sciences [q-bio], Cell type, Multiprotein complex, Nphp, Rpgrip1, Biology, Cell Membrane Structures, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Antigens, Neoplasm, biology.animal, Animals, Humans, Cilia, Molecular Biology, Adaptor Proteins, Signal Transducing, General Immunology and Microbiology, Proteins, Fibroblasts, Embryo, Mammalian, biology.organism_classification, Embryonic stem cell, Mice, Inbred C57BL, Cytoskeletal Proteins, HEK293 Cells, 030104 developmental biology, ciliopathies, Cell Adhesion, Polarity & Cytoskeleton, Carrier Proteins, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Ciliopathies are life-threatening human diseases caused by defective cilia. They can often be traced back to mutations of genes encoding transition zone (TZ) proteins demonstrating that the understanding of TZ organisation is of paramount importance. The TZ consists of multimeric protein modules that are subject to a stringent assembly hierarchy. Previous reports place Rpgrip1l at the top of the TZ assembly hierarchy in Caenorhabditis elegans By performing quantitative immunofluorescence studies in RPGRIP1L-/- mouse embryos and human embryonic cells, we recognise a different situation in vertebrates in which Rpgrip1l deficiency affects TZ assembly in a cell type-specific manner. In cell types in which the loss of Rpgrip1l alone does not affect all modules, additional truncation or removal of vertebrate-specific Rpgrip1 results in an impairment of all modules. Consequently, Rpgrip1l and Rpgrip1 synergistically ensure the TZ composition in several vertebrate cell types, revealing a higher complexity of TZ assembly in vertebrates than in invertebrates.
Published: 2018
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11. Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome

Author: Imen Chabchoub, Didier Lacombe, Marion Sallée, Phillippe Dolhem, Dominique Durand, Karin Dahan, Pierre Ronco, Eric Rondeau, Sylvie Cloarec, Julien Hogan, Gérard Champion, David Ribes, Hubert Nivet, Laurent Mesnard, Georges Deschênes, Thierry Krummel, Khalil El Karoui, Claire Pouteil Noble, Christine Pietrement, Yahsou Delmas, Olivier Gribouval, Olivia Boyer, Tim Ulinski, N. Mohsin, Patrick Niaudet, Guillaume Dorval, Aurélie Hummel, Vanesa Martinez-Barquero, Mongia Hachicha, Véronique Baudouin, Corinne Antignac, Marie-Josèphe Tête, Michel Fischbach, Paloma Maria Parvex, Hassib Chehade, Rémi Salomon, Brigitte Llanas, Dominique Chauveau, Jacques Dantal, Jean-Pierre Grünfeld, S. Benoit, Nassim Kamar, Loïc de Pontual, Eduardo Machuca, Pierre Cochat, Vincent Guigonis, Maryvonne Hourmant, Zelal Ekinci, Chokri Chouchane, Michel Tsimaratos, Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Molecular bases of hereditary kidney diseases: nephronophthisis and hypodysplasia (Equipe Inserm U1163), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hedi Chaker Hospital [Sfax], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Monastir - University of Monastir (UM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Département de Pédiatrie, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institute of Pathology and Genetics, Immunointervention dans les allo et xénotransplantations, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)-ITUN, Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Service de néphrologie et pédiatrie générale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre hospitalier de Saint-Quentin, Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA), Kocaeli Academy for Solidarity, Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Service de Pédiatrie, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de néphrologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Référence du Sud Ouest des Maladies Rénales Rares, CHU Toulouse [Toulouse]-Hôpital des Enfants, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sultan Qaboos University (SQU), Service de Néphrologie, Hôpital de Clocheville, Geneva University Hospital (HUG), Centre Hospitalier Universitaire de Reims (CHU Reims)-American Memorial Hospital (Reims), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Tenon [APHP], Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Néphrologie Pédiatrique [Trousseau], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jean Verdier [AP-HP], CHU Tenon [AP-HP], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Glucocorticoids/therapeutic use, Adult, Male, Nephrotic Syndrome, Adolescent, Nephrotic Syndrome/drug therapy/genetics, 030232 urology & nephrology, Disease, Biology, medicine.disease_cause, HLA-DQ alpha-Chains, 03 medical and health sciences, Genetic Heterogeneity, Young Adult, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], HLA-DQ alpha-Chains/genetics, medicine, Humans, Genetic Predisposition to Disease, Young adult, Preschool, Child, Gene, Glucocorticoids, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, ddc:618, Membrane Glycoproteins, Genetic heterogeneity, Infant, Sequence Analysis, DNA, Membrane Glycoproteins/genetics, Middle Aged, medicine.disease, 3. Good health, DNA/methods, 030104 developmental biology, Nephrology, Child, Preschool, Pediatrics, Perinatology and Child Health, Cohort, Female, Nephrotic syndrome, Sequence Analysis
Abstract: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p
Published: 2018
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12. Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

Author: Geoffroy, Véronique, Stoetzel, Corinne, Scheidecker, Sophie, Schaefer, Elise, Perrault, Isabelle, Bär, Séverine, Kröll, Ariane, Delbarre, Marion, Antin, Manuela, Leuvrey, Anne-Sophie, Henry, Charline, Blanché, Hélène, Decker, Eva, Kloth, Katja, Klaus, Günter, Mache, Christoph, Martin-Coignard, Dominique, McGinn, Steven, Boland, Anne, Deleuze, Jean-François, Friant, Sylvie, Saunier, Sophie, Rozet, Jean-Michel, Bergmann, Carsten, Dollfus, Hélène, Muller, Jean, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Les Hôpitaux Universitaires de Strasbourg (HUS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Philipps Universität Marburg = Philipps University of Marburg, Medical University of Graz, Centre Hospitalier Le Mans (CH Le Mans), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des Maladies Rénales Héréditaires = Laboratory of Hereditary Kidney Diseases (Equipe Inserm U1163 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University Hospital Freiburg, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, and Hôpitaux Universitaires de Strasbourg
Subjects: Male, [SDV.GEN]Life Sciences [q-bio]/Genetics, Heterozygote, Cerebellar Ataxia, Whole Genome Sequencing, [SDV]Life Sciences [q-bio], Homozygote, copy number variation, structural variation, Exons, Alu-mediated recombination, Ciliopathies, Pedigree, Phenotype, whole-genome sequencing, Alu Elements, IFT140, Mainzer-Saldino syndrome, Databases, Genetic, Mutation, tandem duplication, Humans, Female, Carrier Proteins, Retinitis Pigmentosa
Abstract: International audience; Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases. Using whole-genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27-30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole-exome sequencing. Pathogenicity of the mutation was assessed on the patients' skin fibroblasts. Several hundreds of patients with a ciliopathy phenotype were screened and biallelic mutations were identified in 11 families representing 12 pathogenic variants of which seven are novel. Among those unrelated families especially with a Mainzer-Saldino syndrome, eight carried the same tandem duplication (two at the homozygous state and six at the heterozygous state). In conclusion, we demonstrated the implication of structural variations in IFT140-related diseases expanding its mutation spectrum. We also provide evidences for a unique genomic event mediated by an Alu-Alu recombination occurring on a shared haplotype. We confirm that whole-genome sequencing can be instrumental in the ability to detect structural variants for genomic disorders.
Published: 2018
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13. Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans

Author: Philippe Khau Van Kien, Flora Silbermann, Cécile Jeanpierre, Bharti Morar, Alexandre Benmerah, Camille Humbert, Rémi Salomon, Marie-José Perez, Luba Kalaydjieva, Mohammed Zarhrate, Cécile Masson, Patricia Blanchet, Corinne Antignac, Joelle Roume, Brigitte Leroy, Laurence Heidet, Sophie Saunier, Yuliya Petrov, Frédéric Tores, Olivier Gribouval, Mélanie Parisot, Benmerah, Alexandre, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The University of Western Australia (UWA), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], and Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA)
Subjects: Male, Pathology, 030232 urology & nephrology, Kidney development, [SDV.GEN] Life Sciences [q-bio]/Genetics, Kidney, medicine.disease_cause, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 0302 clinical medicine, Genetics(clinical), [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Homozygote, Hypoplasia, Pedigree, 3. Good health, Bilateral Renal Agenesis, medicine.anatomical_structure, Female, Kidney Diseases, Erratum, Integrin alpha Chains, medicine.medical_specialty, Genes, Recessive, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Congenital Abnormalities, 03 medical and health sciences, Fetus, Report, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Renal agenesis, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Dysplasia, Urogenital Abnormalities, business, 030217 neurology & neurosurgery
Abstract: International audience; Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease.
Published: 2014
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14. Nephrocystins play a crucial role in renal epithelial morphogenesis via the regulation of Wnt/PCP components Dishevelled and Rho GTPases

Author: Marion Delous, Cécile Burcklé, Helori-Mael Gaudé, Valentina Grampa, Christine Vesque, Fabiola Terzi, Sophie Saunier, E Montenont, Cécile Jeanpierre, Sylvie Schneider-Maunoury, Flora Silbermann, Corinne Antignac, Rodrick Montjean, BMC, Ed., Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Regionalisation du cerveau des vertébrés - Organogenèse précoce chez la souris et maladies génétiques associées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche Croissance et signalisation ( UMR_S 845 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: RHOA, Morphogenesis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Kidney morphogenesis, 03 medical and health sciences, 0302 clinical medicine, Ciliogenesis, Zebrafish, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Wnt signaling pathway, Cell migration, Cell Biology, biology.organism_classification, 3. Good health, Dishevelled, Cell biology, chemistry, Poster Presentation, biology.protein, 030217 neurology & neurosurgery
Abstract: Nephronophthisis, a hereditary nephropathy characterized by interstitial fibrosis and cyst formation, is caused by mutations in NPHP genes encoding the ciliary proteins called nephrocystins. We investigate the function of nephrocystin-1, -4 and -8, in vitro and in vivo in mammalian kidney cells and in zebrafish respectively. Depletion of either NPHP1 (N1-KD), NPHP4 (N4-KD) or NPHP8 (N8-KD) by shRNA-mediated knockdown in MDCK cells led to abnormal ciliogenesis and epithelial morphogenesis defects in 3D culture. Moreover nephrocystin-4 modulates the Wnt pathways during morphogenesis of the zebrafish pronephros and in vitro, via proteasomal degradation of cytoplasmic/membranous dishevelled. In addition, we demonstrate that nephrocystin-8 is required for dishevelled stability at the basal body essential for proper PCP. In either N1-KD or N4-KD cells, we also showed an over activation of Cdc42 and RhoA, downstream targets of dishevelled. This was accompanied by actin cytoskeletal disorganization, enhanced spreading on collagen, over-activation of proteins that regulate focal adhesion structures i.e p130cas-Pyk2 and increased cell migration. Interestingly, the stable expression of dominant negative form of Cdc42 in knockdown cells rescued the migration and the 3D phenotypes. In parallel, we observed that loss of Nphp4 in mice caused cystic tubular dilatation after subtotal nephrectomy correlated with alteration of ciliogenesis and over activation of Cdc42 and RhoA. Our data show a role of nephrocystins in epithelial cell organization and kidney morphogenesis via the regulation of the Wnt/PCP components including dishevelled and the Rho GTPases.

15. APOL1 polymorphisms and development of CKD in an identical twin donor and recipient pair.: Kidney donation in twins with APOL1 variant

Author: Kofman, Tomek, Audard, Vincent, Narjoz, Céline, Gribouval, Olivier, Matignon, Marie, Leibler, Claire, Desvaux, Dominique, Lang, Philippe, Grimbert, Philippe, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Guellaen, Georges
Subjects: MESH: Living Donors, MESH: Humans, urogenital system, MESH: Renal Insufficiency, Chronic, MESH: Genetic Predisposition to Disease, APOL1 polymorphism, kidney transplantation, MESH: Follow-Up Studies, MESH: Kidney, MESH: Lipoproteins, HDL, MESH: Male, MESH: Kidney Transplantation, MESH: Genotype, MESH: Biopsy, MESH: Apolipoproteins, MESH: Young Adult, MESH: Polymorphism, Genetic, outcome, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Twins, Monozygotic, MESH: Diseases in Twins, donor
Abstract: International audience; We report an occurrence of progressive loss of transplant function and ultimately transplant failure after living related kidney transplantation involving monozygotic twin brothers of Afro-Caribbean origin who were both heterozygous for the G1 and G2 kidney disease risk alleles in the APOL1 gene, which encodes apolipoprotein L-I. A 21-year-old man with end-stage kidney disease of unknown cause received a kidney from his brother, who was confirmed as a monozygotic twin by microsatellite analysis. Thirty months after transplantation, the patient presented with proteinuria and decreased estimated glomerular filtration rate; a biopsy of the transplant showed typical focal segmental glomerulosclerosis lesions. He received steroid therapy, but progressed to kidney failure 5 years later. The twin brother had normal kidney function without proteinuria at the time of transplantation; however, 7 years later, he was found to have decreased estimated glomerular filtration rate (40mL/min/1.73m(2)) and proteinuria (protein excretion of 2.5g/d). APOL1 genotyping revealed that both donor and recipient were heterozygous for the G1 and G2 alleles. This case is in stark contrast to the expected course of kidney transplantation in identical twins and suggests a role for APOL1 polymorphisms in both the donor and recipient.
Published: 2014
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16. TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia

Author: Body-Bechou, Delphine, Loget, Philippe, d'Herve, Dominique, Le Fiblec, Bernard, Grebille, Anne-Gaelle, Le Guern, Hélène, Labarthe, Caroline, Redpath, Margaret, Cabaret-Dufour, Anne-Sophie, Odent, Sylvie, Fievet, Alice, Antignac, Corinne, Heidet, Laurence, Taque, Sophie, Patrice, Poulain, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Clinique mutualiste La Sagesse, Centre Pluridisciplinaire de Diagnostic Prénatal, Centre hospitalier Saint-Brieuc, Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie Pédiatrique, AP-HP, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Service d'Hématologie et d'Oncologie pédiatrique, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, Heterozygote, [SDV.GEN]Life Sciences [q-bio]/Genetics, Gestational Age, Oligohydramnios, Clubfoot, Phenotype, Pregnancy, Mutation, Humans, Prenatal, Female, Multicystic Dysplastic Kidney, Pancreas, Hepatocyte Nuclear Factor 1-beta, Ultrasonography
Abstract: International audience; OBJECTIVE: The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. METHODOLOGY: We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. CASES: Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. CONCLUSION: TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.
Published: 2014
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17. Role of the protein complex NPHP1/NPHP4/RPGRIP1L involved in Nephronophthisis and associated ciliopathies, in epithelial morphogenesis, cell polarity and ciliogenesis

Author: Gaudé, Helori-Mael, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université René Descartes - Paris V, Sophie Saunier, and STAR, ABES
Subjects: NPHP1, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, Ciliopathy, RPGRIP1L, Polarité cellulaire, Wnt signaling, Ciliopathie, Dishevelled, Nephronophthisis, Néphronophtise, Cell polarity, Voie de signalisation Wnt, NPHP4
Abstract: Nephronophthisis, a hereditary nephropathy characterized by interstitial fibrosis and cyst formation, is caused by mutations in NPHP genes encoding the ciliary proteins called nephrocystins. We investigate the function of nephrocystin-1, -4 and -8, in vitro and in vivo in mammalian kidney cells and in zebrafish respectively. Depletion of either NPHP1 (N1-KD), NPHP4 (N4-KD) or RPGRIP1L (RPGRIP1L-KD) by shRNA-mediated knockdown in MDCK cells led to abnormal ciliogenesis, delay in tight junction formation and disorganized structures in 3D culture. Moreover NPHP4 modulates the Wnt pathways during morphogenesis of the zebrafish pronephros and in mammalian kidney cells in which NPHP4 interacts with inversin and dishevelled, regulating its stability and its subcellular localization. Rpgrip1l is required for dishevelled stabilization at the cilium base and is necessary for polarized positioning of motile cilia of the zebrafish floor plate and sensory hair cells of the mouse cochlea. In either N1-KD or N4-KD cells, we also showed an over activation of Cdc42 and RhoA, downstream targets of dishevelled. This was accompanied by actin cytoskeletal disorganization, enhanced spreading on collagen, over-activation of proteins that regulate focal adhesion structures i.e p130cas-Pyk2 and increased cell migration. Interestingly, the stable expression of dominant negative form of Cdc42 in knockdown cells rescued the migration and the 3D phenotypes. In parallel, we observed that loss of Nphp4 in mice caused cystic tubular dilatation after subtotal nephrectomy correlated with alteration of ciliogenesis and over activation of Cdc42 and RhoA. Our data show a role of nephrocystins in epithelial cell organization and kidney morphogenesis in particular in regulation of focal adhesion, tight junction, ciliogenesis via dishevelled stability., La néphronophtise (NPH) est une néphropathie tubulo-interstitielle chronique de transmission autosomique récessive. Elle représente la cause génétique la plus fréquente des insuffisances rénales terminales de l’enfant et du jeune adulte (5 à 10%). Elle se caractérise au niveau histologique par des anomalies des membranes basales tubulaires, une fibrose interstitielle massive et par l’apparition tardive de kystes à la jonction cortico-médullaire. Dans 40% des cas, la NPH est associée à des atteintes extra-rénales, notamment oculaires, cérébelleuses ou osseuses, définissant de nombreux syndromes (Senior Løken, Joubert, Jeune, etc). Sur la quinzaine de gènes responsables de la maladie, sept ont été identifiés au laboratoire : NPHP1, NPHP4, NPHP8/RPGRIP1L, NPHP11/MKS3, NPHP12/TTC21B, NPHP13/WDR19 et IFT140. Les protéines codées par ces gènes forment des complexes moléculaires principalement localisés au niveau des jonctions cellulaires et du cil primaire des cellules épithéliales rénales, classifiant la NPH et les syndromes associés dans le groupe des "ciliopathies". Mes travaux de thèse se sont intégrés au projet de recherche de l'équipe, centré sur l'étude des mécanismes pathophysiologiques à l'origine des lésions observées dans la NPH. Pour cela, nous avons développé des modèles de cellules tubulaires rénales (MDCK, IMCD et HEK293), et des modèles animaux (souris et poisson zèbre en collaboration avec l'équipe de Sylvie Schneider-Maunoury UMR7622). Je me suis particulièrement intéressé à l'analyse des phénotypes cellulaires et à la caractérisation des voies de signalisation perturbées dans les cellules épithéliales rénales invalidées pour les gènes NPHP1, NPHP4 et NPHP8/RPGRIP1L. Les protéines codées par ces gènes forment un complexe au niveau du cil primaire et des jonctions cellulaires. J'ai participé à définir le rôle crucial de ces protéines dans l’établissement des jonctions serrées par leur interaction avec les protéines de polarité, la morphogénèse épithéliale en culture 3D et la ciliogenèse. De plus, j'ai mis en évidence que l'absence de ces protéines entraîne des anomalies de migration et d'adhésion cellulaires s’accompagnant d’une activation anormale des protéines Rho GTPases (Cdc42, Rac1 et RhoA) et d’une réorganisation du cytosquelette d’actine. J'ai par ailleurs montré que le complexe NPHP4/inversine/RPGRIP1L régule finement l'expression et la localisation de Dishevelled, élément clé des voies Wnt canonique et Wnt/PCP, dans les cellules rénales. Ceci est en accord avec les défauts de polarité planaire observés dans le pronéphros du poisson zèbre et dans le rein de la souris, après invalidation des gènes Nphp4 ou Rpgrip1l. L'ensemble de ces résultats a permis de mieux comprendre le rôle moléculaire et cellulaire des néphrocystines et les mécanismes pathophysiologiques aboutissant aux altérations retrouvées chez les patients telles que la fibrose interstitielle rénale et la formation de kystes.
Published: 2012

18. Rôle du complexe protéique NPHP1/NPHP4/RPGRIP1L impliqué dans la néphronophtise et les ciliopathies associées, dans la morphogenèse épithéliale, la polarité cellulaire et la ciliogenèse

Author: Gaudé, Helori-Mael, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université René Descartes - Paris V, and Sophie Saunier
Subjects: NPHP1, Dishevelled, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Nephronophthisis, Néphronophtise, Ciliopathy, Cell polarity, RPGRIP1L, Polarité cellulaire, Voie de signalisation Wnt, Wnt signaling, Ciliopathie, NPHP4
Abstract: Nephronophthisis, a hereditary nephropathy characterized by interstitial fibrosis and cyst formation, is caused by mutations in NPHP genes encoding the ciliary proteins called nephrocystins. We investigate the function of nephrocystin-1, -4 and -8, in vitro and in vivo in mammalian kidney cells and in zebrafish respectively. Depletion of either NPHP1 (N1-KD), NPHP4 (N4-KD) or RPGRIP1L (RPGRIP1L-KD) by shRNA-mediated knockdown in MDCK cells led to abnormal ciliogenesis, delay in tight junction formation and disorganized structures in 3D culture. Moreover NPHP4 modulates the Wnt pathways during morphogenesis of the zebrafish pronephros and in mammalian kidney cells in which NPHP4 interacts with inversin and dishevelled, regulating its stability and its subcellular localization. Rpgrip1l is required for dishevelled stabilization at the cilium base and is necessary for polarized positioning of motile cilia of the zebrafish floor plate and sensory hair cells of the mouse cochlea. In either N1-KD or N4-KD cells, we also showed an over activation of Cdc42 and RhoA, downstream targets of dishevelled. This was accompanied by actin cytoskeletal disorganization, enhanced spreading on collagen, over-activation of proteins that regulate focal adhesion structures i.e p130cas-Pyk2 and increased cell migration. Interestingly, the stable expression of dominant negative form of Cdc42 in knockdown cells rescued the migration and the 3D phenotypes. In parallel, we observed that loss of Nphp4 in mice caused cystic tubular dilatation after subtotal nephrectomy correlated with alteration of ciliogenesis and over activation of Cdc42 and RhoA. Our data show a role of nephrocystins in epithelial cell organization and kidney morphogenesis in particular in regulation of focal adhesion, tight junction, ciliogenesis via dishevelled stability.; La néphronophtise (NPH) est une néphropathie tubulo-interstitielle chronique de transmission autosomique récessive. Elle représente la cause génétique la plus fréquente des insuffisances rénales terminales de l’enfant et du jeune adulte (5 à 10%). Elle se caractérise au niveau histologique par des anomalies des membranes basales tubulaires, une fibrose interstitielle massive et par l’apparition tardive de kystes à la jonction cortico-médullaire. Dans 40% des cas, la NPH est associée à des atteintes extra-rénales, notamment oculaires, cérébelleuses ou osseuses, définissant de nombreux syndromes (Senior Løken, Joubert, Jeune, etc). Sur la quinzaine de gènes responsables de la maladie, sept ont été identifiés au laboratoire : NPHP1, NPHP4, NPHP8/RPGRIP1L, NPHP11/MKS3, NPHP12/TTC21B, NPHP13/WDR19 et IFT140. Les protéines codées par ces gènes forment des complexes moléculaires principalement localisés au niveau des jonctions cellulaires et du cil primaire des cellules épithéliales rénales, classifiant la NPH et les syndromes associés dans le groupe des "ciliopathies". Mes travaux de thèse se sont intégrés au projet de recherche de l'équipe, centré sur l'étude des mécanismes pathophysiologiques à l'origine des lésions observées dans la NPH. Pour cela, nous avons développé des modèles de cellules tubulaires rénales (MDCK, IMCD et HEK293), et des modèles animaux (souris et poisson zèbre en collaboration avec l'équipe de Sylvie Schneider-Maunoury UMR7622). Je me suis particulièrement intéressé à l'analyse des phénotypes cellulaires et à la caractérisation des voies de signalisation perturbées dans les cellules épithéliales rénales invalidées pour les gènes NPHP1, NPHP4 et NPHP8/RPGRIP1L. Les protéines codées par ces gènes forment un complexe au niveau du cil primaire et des jonctions cellulaires. J'ai participé à définir le rôle crucial de ces protéines dans l’établissement des jonctions serrées par leur interaction avec les protéines de polarité, la morphogénèse épithéliale en culture 3D et la ciliogenèse. De plus, j'ai mis en évidence que l'absence de ces protéines entraîne des anomalies de migration et d'adhésion cellulaires s’accompagnant d’une activation anormale des protéines Rho GTPases (Cdc42, Rac1 et RhoA) et d’une réorganisation du cytosquelette d’actine. J'ai par ailleurs montré que le complexe NPHP4/inversine/RPGRIP1L régule finement l'expression et la localisation de Dishevelled, élément clé des voies Wnt canonique et Wnt/PCP, dans les cellules rénales. Ceci est en accord avec les défauts de polarité planaire observés dans le pronéphros du poisson zèbre et dans le rein de la souris, après invalidation des gènes Nphp4 ou Rpgrip1l. L'ensemble de ces résultats a permis de mieux comprendre le rôle moléculaire et cellulaire des néphrocystines et les mécanismes pathophysiologiques aboutissant aux altérations retrouvées chez les patients telles que la fibrose interstitielle rénale et la formation de kystes.
Published: 2012

19. Dishevelled stablisation at the cilium by RPGRIP1L is essential for planar cell polarity

Author: Sylvie Schneider-Maunoury, Christine Vesque, Hm Gaudé, Mireille Montcouquiol, Isabelle Anselme, Flora Silbermann, Margot Leroux-Berger, Sophie Saunier, Alexia Mahuzier, BMC, Ed., Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie du système nerveux central - Institut François Magendie, and Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: animal structures, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, 0302 clinical medicine, GLI3, Basal body, lcsh:QH573-671, Zebrafish, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Floor plate, chemistry.chemical_classification, 0303 health sciences, lcsh:Cytology, Cilium, Ciliary transition zone, Cell Biology, biology.organism_classification, Dishevelled, Cell biology, [SDV.TOX] Life Sciences [q-bio]/Toxicology, chemistry, RPGRIP1L, [SDV.TOX]Life Sciences [q-bio]/Toxicology, embryonic structures, Oral Presentation, 030217 neurology & neurosurgery
Abstract: Cilia are involved in planar polarity in different systems but the mechanisms by which they influence the polarization process are unclear [1]. In order to clarify this issue, we investigated the function of the ciliary gene Rpgrip1l (Ftm/NPHP8/MKS5) in the mammalian cochlear sensory epithelium and in the zebrafish floor plate. We and others have previously shown that mutations in the human RPGRIP1L gene cause Meckel and Joubert type B syndromes [2]. The Rpgrip1l protein is localised at the ciliary transition zone and is required for transduction of the Hh/ Gli pathway [3]. Our recent work has shown that Rpgrip1l patterns the telencephalon via the regulation of Gli3 proteolytic cleavage [4]. Here we show that in both the mammalian cochlear sensory epithelium and the zebrafish floor plate, Rpgrip1l is required for correct positioning of the basal body along the planar polarity axis. Our results strongly suggest that Rpgrip1l is essential for stabilizing the adaptor protein dishevelled at the basal body and/or cilium. Finally, we demonstrate that, in the zebrafish floor plate, the function of Rpgrip1l in basal body positioning is mediated by dishevelled. We propose that Rpgrip1l participates in a protein complex required for stabilizing dishevelled at the cilium, and that this stabilization is essential for asymmetric localization of the basal body along the planar polarity axis.
Published: 2012

20. Dishevelled stabilization by the ciliopathy protein Rpgrip1l is essential for planar cell polarity

Author: Isabelle Anselme, Mireille Montcouquiol, Sophie Saunier, Alexia Mahuzier, Christine Vesque, Sylvie Schneider-Maunoury, Helori-Mael Gaudé, Jerome Ezan, Flora Silbermann, Valentina Grampa, Delphine Delacour, Margot Leroux-Berger, Regionalisation du cerveau des vertébrés - Organogenèse précoce chez la souris et maladies génétiques associées, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université Pierre et Marie Curie, the Agence Nationale de la Recherche grant R07089KS, Association pour la Recherche sur le Cancer 4951XA0731F and SFI20101201851, the Fondation pour la Recherche Médicale ('Equipe FRM' grant DEQ20071210558, the Association pour l'Utilization du Rein Artificiel (AURA), the Société de Néphrologie, the Association pour l'Information et la Recherche sur les maladies Rénales Génétiques (AIRG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: animal structures, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, stomatognathic system, Cell polarity, medicine, Basal body, Animals, Cilia, Cytoskeleton, Zebrafish, Research Articles, 030304 developmental biology, Floor plate, chemistry.chemical_classification, 0303 health sciences, biology, Cilium, fungi, Cell Polarity, Proteins, Cell Biology, Zebrafish Proteins, medicine.disease, biology.organism_classification, Dishevelled, Cell biology, Cochlea, Mice, Inbred C57BL, Ciliopathy, Cytoskeletal Proteins, chemistry, embryonic structures, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Rpgrip1l is required for planar localization of the basal body and acts within a ciliopathy protein complex by stabilizing dishevelled., Cilia are at the core of planar polarity cellular events in many systems. However, the molecular mechanisms by which they influence the polarization process are unclear. Here, we identify the function of the ciliopathy protein Rpgrip1l in planar polarity. In the mouse cochlea and in the zebrafish floor plate, Rpgrip1l was required for positioning the basal body along the planar polarity axis. Rpgrip1l was also essential for stabilizing dishevelled at the cilium base in the zebrafish floor plate and in mammalian renal cells. In rescue experiments, we showed that in the zebrafish floor plate the function of Rpgrip1l in planar polarity was mediated by dishevelled stabilization. In cultured cells, Rpgrip1l participated in a complex with inversin and nephrocystin-4, two ciliopathy proteins known to target dishevelled to the proteasome, and, in this complex, Rpgrip1l prevented dishevelled degradation. We thus uncover a ciliopathy protein complex that finely tunes dishevelled levels, thereby modulating planar cell polarity processes.
Published: 2012
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21. The ERA-EDTA Working Group on inherited kidney disorders

Author: Corinne Antignac, Patrick H. Maxwell, Giuseppe Remuzzi, Franz Schaefer, Francesco Emma, Albert C.M. Ong, Dominique Chauveau, Olivier Devuyst, René J. M. Bindels, Pierre Ronco, Ron T. Gansevoort, RONCO, Pierre, Institute of Physiology, Universität Zürich [Zürich] = University of Zurich (UZH)-Zurich Center for Integrative Human Physiology, Klinik für Nephrologie, UniversitätsSpital, Division of Nephrology, UCL Medical School, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Physiology, Radboud University Medical Center [Nijmegen], Service de Néphrologie - Immunologie Clinique [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-PRES Université de Toulouse, Division of Nephrology and Dialysis, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Department of Nephrology, University Medical Center, University of Groningen, UCL Division of Medicine, University College of London [London] (UCL), Kidney Genetics Group, University of Sheffield Medical School, Mario Negri Institute for Pharmacological Research, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Division of Pediatric Nephrology, Universität Heidelberg [Heidelberg], Center for Rare Diseases, Universität Heidelberg [Heidelberg]-University Medicine Heidelberg, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), University of Zurich, Devuyst, Olivier, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse]-PRES Université de Toulouse, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Pathology, 2747 Transplantation, cystic diseases, medicine.medical_treatment, 030232 urology & nephrology, Physiology, tubulopathies, 10052 Institute of Physiology, MESH: Kidney Transplantation, 0302 clinical medicine, 10035 Clinic for Nephrology, genetics, MESH: Renal Dialysis, 030212 general & internal medicine, Societies, Medical, Cystic disease, 2727 Nephrology, MESH: Genetic Predisposition to Disease, rare diseases, MESH: Nephrology, 3. Good health, Clinical Practice, Europe, Nephrology, 10076 Center for Integrative Human Physiology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Kidney Diseases, Hemodialysis, medicine.medical_specialty, MESH: Societies, Medical, 610 Medicine & health, patient organization, 03 medical and health sciences, Renal Dialysis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Genetic Predisposition to Disease, Cystic diseases, Transplantation, MESH: Kidney Diseases, MESH: Humans, business.industry, urogenital system, medicine.disease, Patient organization, Kidney Transplantation, Membrane transport and intracellular motility Renal disorder [NCMLS 5], CLINICAL-PRACTICE, 570 Life sciences, biology, Kidney disorder, MESH: Europe, business, Kidney disease
Abstract: International audience; Dozens of inherited diseases affect the kidney; collectively, they account for at least 10% of patients with end-stage renal disease in Europe [1]. The underlying genetic defects may affect all structures and cell types of the nephron and may therefore compromise all aspects of kidney function. In addition, extra-renal involvement is frequently associated. In terms of frequency, inherited kidney disorders vary from relatively frequent diseases, such as autosomal dominant polycystic kidney disease (ADPKD, that arguably affects one in every 1000 person), to 'rare' diseases that, by definition, affect less than five persons in every 10 000.
Published: 2012
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22. Loss-of-function point mutations associated with renal tubular dysgenesis provide insights about renin function and cellular trafficking

Author: Laurent Muller, Jean-Marie Gasc, Maud Clemessy, Daniel Bur, Marie-Claire Gubler, Olivier Gribouval, Xavier Iturrioz, Pierre Corvol, Annie Michaud, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paul Verlaine - Metz (UPVM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Angiogénèse embryonnaire et pathologique, Iturrioz, Xavier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, [SDV]Life Sciences [q-bio], Mutant, medicine.disease_cause, Kidney Tubules, Proximal, 0302 clinical medicine, Pregnancy, Cricetinae, Gene duplication, [CHIM] Chemical Sciences, Renin, Missense mutation, Genetics (clinical), Cellular localization, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Mutation, General Medicine, Recombinant Proteins, 3. Good health, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV] Life Sciences [q-bio], Protein Transport, Female, medicine.medical_specialty, Molecular Sequence Data, CHO Cells, Biology, Cell Line, 03 medical and health sciences, Cricetulus, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Renin–angiotensin system, Genetics, medicine, [CHIM]Chemical Sciences, Animals, Humans, Point Mutation, Amino Acid Sequence, Molecular Biology, Loss function, 030304 developmental biology, Point mutation, Protein Structure, Tertiary, Endocrinology, Urogenital Abnormalities, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: Renal tubular dysgenesis (RTD) is a recessive autosomal disease characterized by persistent fetal anuria and perinatal death. During the systematic screening of mutations of the different genes of the renin-angiotensin system associated with RTD, two missense mutations in the renin gene were previously identified, the first affects one of the two catalytic aspartates (D38N) of renin, and the second, S69Y, is located upstream of the 'flap', a mobile β-hairpin structure which covers the substrate-binding site of renin. Here we report a novel renin mutation leading to the duplication of the tyrosine residue Y15dup, homologous to Y9 in some other aspartyl proteases, which seems to play a crucial role along the activation pathway. The biochemical and cellular mechanisms underlying renin inactivation were investigated. We expressed prorenin constructs harboring the identified point mutations in two established cell lines, able (AtT-20 cells) or unable (CHO cells) to process prorenin to renin and we evaluated the cellular localization of renin mutants and their functional properties. All three mutants were misfolded to different levels, were enzymatically inactive and exhibited abnormal intracellular trafficking. We suggest a misfolding of Y15dup renin, a partial misfolding of D38N prorenin and a misfolding of S69Y prorenin leading to complete absence of secretion. The structural consequences of the renin mutations were estimated by molecular modeling, which suggested some important structural alterations. This is the first characterization of the mechanisms underlying loss of renin function in RTD.
Published: 2010
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23. The ciliary pocket: an endocytic membrane domain at the base of primary and motile cilia

Author: Alain Schmitt, Nathalie Spassky, Flora Silbermann, Kelly Romeo, Rania Ghossoub, Alexandre Benmerah, Anahi Molla-Herman, Alice Meunier, Philippe Bastin, Catherine Serres, Thierry Blisnick, Sophie Saunier, Chris Emmerson, Pierre Bourdoncle, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie cellulaire des Trypanosomes - Trypanosome Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), The present work was partially funded by a grant from the ANR ‘GENOPAT 2009’ (R09088KS to S.S., A.B. and P.B.). Research at Institut Pasteur was funded by the Institut Pasteur and the CNRS., Biologie cellulaire des Trypanosomes, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Ovulation, [SDV]Life Sciences [q-bio], Flagellum, Biology, Epithelium, Cell Line, Mice, 03 medical and health sciences, Membrane Microdomains, 0302 clinical medicine, Cell Movement, Intraflagellar transport, Animals, Humans, Cilia, Cytoskeleton, Zona Pellucida, Actin, 030304 developmental biology, 0303 health sciences, Undulipodium, Cilium, Cell Biology, Fibroblasts, Actins, Endocytosis, Cell biology, Mice, Inbred C57BL, Flagella, Ciliary pocket, Motile cilium, Female, 030217 neurology & neurosurgery
Abstract: International audience; Cilia and flagella are eukaryotic organelles involved in multiple cellular functions. The primary cilium is generally non motile and found in numerous vertebrate cell types where it controls key signalling pathways. Despite a common architecture, ultrastructural data suggest some differences in their organisation. Here, we report the first detailed characterisation of the ciliary pocket, a depression of the plasma membrane in which the primary cilium is rooted. This structure is found at low frequency in kidney epithelial cells (IMCD3) but is associated with virtually all primary cilia in retinal pigment epithelial cells (RPE1). Transmission and scanning electron microscopy, immunofluorescence analysis and videomicroscopy revealed that the ciliary pocket establishes closed links with the actin-based cytoskeleton and that it is enriched in active and dynamic clathrin-coated pits. The existence of the ciliary pocket was confirmed in mouse tissues bearing primary cilia (cumulus), as well as motile cilia and flagella (ependymal cells and spermatids). The ciliary pocket shares striking morphological and functional similarities with the flagellar pocket of Trypanosomatids, a trafficking-specialised membrane domain at the base of the flagellum. Our data therefore highlight the conserved role of membrane trafficking in the vicinity of cilia.
Published: 2010
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23 results on '"Néphropathies héréditaires et rein en développement (UMR_S 983)"'

1. APOL1 polymorphisms and development of CKD in an identical twin donor and recipient pair. : Kidney donation in twins with APOL1 variant

2. Allo-Immune Membranous Nephropathy and Recombinant Aryl Sulfatase Replacement Therapy: A Need for Tolerance Induction Therapy

3. The kidney as a reservoir for HIV-1 after renal transplantation

4. Mainzer-Saldino syndrome is a ciliopathy caused by mutations in the IFT140 gene

5. Alteration of nephrocystins and IFT-A proteins causes similar ciliary phenotypes leading to Nephronophthisis

6. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy

7. RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects

8. Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome

9. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

10. Cell type‐specific regulation of ciliary transition zone assembly in vertebrates

11. Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome

12. Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

13. Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans

14. Nephrocystins play a crucial role in renal epithelial morphogenesis via the regulation of Wnt/PCP components Dishevelled and Rho GTPases

15. APOL1 polymorphisms and development of CKD in an identical twin donor and recipient pair.: Kidney donation in twins with APOL1 variant

16. TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia

17. Role of the protein complex NPHP1/NPHP4/RPGRIP1L involved in Nephronophthisis and associated ciliopathies, in epithelial morphogenesis, cell polarity and ciliogenesis

18. Rôle du complexe protéique NPHP1/NPHP4/RPGRIP1L impliqué dans la néphronophtise et les ciliopathies associées, dans la morphogenèse épithéliale, la polarité cellulaire et la ciliogenèse

19. Dishevelled stablisation at the cilium by RPGRIP1L is essential for planar cell polarity

20. Dishevelled stabilization by the ciliopathy protein Rpgrip1l is essential for planar cell polarity

21. The ERA-EDTA Working Group on inherited kidney disorders

22. Loss-of-function point mutations associated with renal tubular dysgenesis provide insights about renin function and cellular trafficking

23. The ciliary pocket: an endocytic membrane domain at the base of primary and motile cilia

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23 results on '"Néphropathies héréditaires et rein en développement (UMR_S 983)"'

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