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1. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author

Ana Patiño-García, Thomas G. P. Grunewald, David G. Cox, Lindsay M. Morton, Michelle Manning, Sandrine Grossetête-Lalami, Gaëlle Pierron, Nadège Corradini, Stephen J. Chanock, Kathleen Wyatt, Udo Kontny, Gregory T. Armstrong, Jean Michon, Sakina Zaidi, Didier Surdez, Wolfgang Hartmann, Heinrich Kovar, Olivier Delattre, Jennifer Kriebel, Nathalie Gaspar, Perrine Marec Bérard, Valérie Laurence, Casey L. Dagnall, Thomas Kirchner, Stéphanie Reynaud, Uta Dirksen, Nathaniel Rothman, Konstantin Strauch, Margaret A. Tucker, Lisa Mirabello, Smita Bhatia, Markus Metzler, Laurie Burdett, Neal D. Freedman, Rebeca Alba Rubio, Franck Tirode, Andreas E. Kulozik, Meredith Yeager, Kristine Jones, Javier Alonso, Stelly Ballet, Olivier Mirabeau, Eve Lapouble, Robert N. Hoover, Weiyin Zhou, Wendy M. Leisenring, Leslie L. Robison, Piero Picci, Javed Khan, Thomas Meitinger, Anna González-Neira, Eric Karlins, Mitchell J. Machiela, Unión Europea, TIRODE, Franck, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Laboratory for Pediatric Sarcoma Biology [Munich, Germany], Ludwig-Maximilian-Universität München Pathologisches Institut [Germany], German Cancer Consortium [Heidelberg] (DKTK), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unité de Génétique Somatique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research (FNLCR), Unité de Génétique Somatique [Institut Curie, Paris], Children’s Cancer Research Institute [Vienna, Austria], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Division of Pediatric Hematology, Oncology and Stem Cell Transplantation [Aechen, Germany], Genotyping Unit (CeGen), Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Istituto Ortopedico Rizzoli [Bologna, Italy], Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Epidemiology and Cancer Control [Memphis, TN, USA], Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA], Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA], University Children's Hospital of Heidelberg [Heidelberg, Germany], Research Unit of Molecular Biology [Neuherberg, Germany], Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Diseases [Neuherberg, Germany] (DZD), Institute of Human Genetics [Neuherberg] (IHG), Helmholtz Zentrum München = German Research Center for Environmental Health, Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen = Uniklinikum Erlangen, Gerhard-Domagk-Institute of Pathology, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Genetic Epidemiology [Neuherberg, Germany], Chair of Genetic Epidemiology [Munich, Germany] (IBE), Institute of Pathology [Munich, Germany], University Children's Hospital of Essen [Essen, Germany], This work was supported by the Intramural Research Program of the U.S. NationalCancer Institute and the Intramural Research Program of the American Cancer Society.This work was supported by grants from the Institut Curie, the Inserm, the LigueNationale Contre le Cancer (Equipe labellisée, Carte d’Identité des Tumeurs programand Recherche Epidémiologique 2009 program), the ANR-10-EQPX-03 from the AgenceNationale de la Recherche, the European PROVABES (ERA-649 NET TRANSCAN JTC2011), and ASSET (FP7-HEALTH-2010-259348) projects. This research was supportedby FP7 grant 'EURO EWING Consortium' No. 602856 and the following associations:Courir pour Mathieu, Dans les pas du Géant, Les Bagouzamanon, Enfants et Santé, M lavie avec Lisa, Lulu et les petites bouilles de lune, les Amis de Claire, l’Etoile de Martin andthe Société Française de lutte contre les Cancers et les leucémies de l’Enfant et del’adolescent. The laboratory of T. G. P. Grünewald is supported by grants from the‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultätder LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMU excellentwithin the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the WilhelmSander-Foundation (2016.167.1), and by the German Cancer Aid (DKH-111886 andDKH-70112257). D. Surdez is supported by SiRIC (Grant « INCa-DGOS-4654). Wethank the following clinicians for providing samples used in this study: C. Alenda, F.Almazán, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Beléndez, C. Berger, C. Bergeron, P. Biron, J.Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D.Chauveaux, C. Calvo, A. Carboné, C. Clement, T. Contra, N. Corradini, A.S. Defachelles,V. Gandemer-Delignieres, A. Deville, A. Echevarria, J. Fayette, M. Fraga, D. Frappaz, J.L.Fuster, P. García-Miguel, J.C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O.Lejars, R. López-Almaraz, B. López-Ibor, P. Lutz, J.F. Mallet, L. Mansuy, P. Marec Bérard,G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G.Margueritte, C. Mata, M.E. Mateos, M. Melo, C. Moscardó, M. Munzer, B. Narciso, A.Navajas, D. Orbach, C. Oudot, H. Pacquement, C. Paillard, Y. Perel, T. Philip, C. Piguet,M.I. Pintor, D. Plantaz, E. Plouvier, S. Ramirez-Del-Villar, I. Ray-Coquard, Y. Reguerre,M. Rios, P. Rohrlich, H. Rubie, A. Sastre, G. Schleiermacher, C. Schmitt, P. Schneider, L.Sierrasesumaga, C. Soler, N. Sirvent, S. Taque, E. Thebaud, A. Thyss, R. Tichit, J.J. Uriz, J.P. Vannier, F. Watelle-Pichon. This work was supported by the Instituto de SaludCarlos III (PI16CIII/00026) and the Asociación Pablo Ugarte, Fundación Sonrisa deAlex, ASION-La Hucha de Tomás, Sociedad Española de Hematología y OncologíaPediátricas. The Childhood Cancer Survivor Study is supported by the NationalCancer Institute (CA55727, G.T. Armstrong, Principal Investigator), with funding forgenotyping from the Intramural Research Program of the National Institutes ofHealth, National Cancer Institute. The KORA study was initiated and financed by theHelmholtz Zentrum München—German Research Center for Environmental Health,which is funded by the German Federal Ministry of Education and Research (BMBF) andby the State of Bavaria. Furthermore, KORA research was supported within the MunichCenter of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part ofLMUinnovativ, Helmholtz-Zentrum München (HZM), University Hospital Erlangen [Germany], Westfälische Wilhelms-Universität Münster (WWU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Candidate gene, Oncogene Proteins, Fusion, Medizin, General Physics and Astronomy, Genome-wide association study, Cell Cycle Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Science, Genetics, Multidisciplinary, Nuclear Proteins, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Homeobox Protein Nkx-2.2, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quality Control, Risk, Genotype, Science, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Genetic Predisposition to Disease, Allele, Alleles, Cell Proliferation, Homeodomain Proteins, Proto-Oncogene Protein c-fli-1, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Zebrafish Proteins, Pediatric cancer, 030104 developmental biology, Expression quantitative trait loci, lcsh:Q, RNA-Binding Protein EWS, Transcription Factors, Genome-Wide Association Study
Abstract

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk., Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.

Published
2018
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2. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism

Author

Maria-Christina Zennaro, Rami M El Zein, Vandana Jain, Laurence Amar, Sheerazed Boulkroun, Ian J. Orozco, Thomas J. Jentsch, Fabio L. Fernandes-Rosa, Hervé Lefebvre, Xavier Jeunemaitre, Georgios Daniil, Thomas Schwarzmayr, Corinna Göppner, Tim M. Strom, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne] (FMP), Leibniz Association, Max Delbrück Centrum für Molekulare Medizin (MDC), Division of Pediatric Endocrinology [New Delhi, India] (Department of Pediatrics), All India Institute of Medical Sciences [New Delhi], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Unité d'hypertension artérielle [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Endocrinologie, Diabète et Maladies Métaboliques [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institute of Human Genetics [Neuherberg] (IHG), Helmholtz Zentrum München = German Research Center for Environmental Health, Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), This work was funded through institutional support from INSERM and by the Agence Nationale pour la Recherche (ANR-13-ISV1-0006-01), the Fondation pour la Recherche Médicale (DEQ20140329556), the Programme Hospitalier de Recherche Clinique (PHRC grant AOM 06179), and by institutional grants from INSERM. The laboratory of Dr. Maria- Christina Zennaro is also partner of the H2020 project ENSAT-HT grant n° 633983. Thomas J. Jentsch was supported by institutional funding from the Leibniz and Helmholtz Associations, a grant from the BMBF (E-RARE 01GM1403) and by the Prix Louis-Jeantet de Médecine., Fernandes Rosa, Fabio, Max-Delbrück-Centrum für Molekulare Medizin [Berlin, Germany] (MDC), and Helmholtz-Zentrum München (HZM)

Subjects
0301 basic medicine, Aldosterone synthase, medicine.medical_specialty, 030209 endocrinology & metabolism, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gating, Biology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Primary aldosteronism, Germline mutation, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetics, medicine, Gain of function mutation, Gene, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, CLCN2, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Aldosterone, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030104 developmental biology, Endocrinology, chemistry, Cardiovascular and Metabolic Diseases, Cancer research, Chloride channel, biology.protein, Function and Dysfunction of the Nervous System, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Primary aldosteronism is the most common and curable form of secondary arterial hypertension. We performed whole-exome sequencing in patients with early-onset primary aldosteronism and identified a de novo heterozygous c.71G>A/p.Gly24Asp mutation in the CLCN2 gene, encoding the voltage-gated ClC-2 chloride channel 1 , in a patient diagnosed at 9 years of age. Patch-clamp analysis of glomerulosa cells of mouse adrenal gland slices showed hyperpolarization-activated Cl- currents that were abolished in Clcn2-/- mice. The p.Gly24Asp variant, located in a well-conserved 'inactivation domain'2,3, abolished the voltage- and time-dependent gating of ClC-2 and strongly increased Cl- conductance at resting potentials. Expression of ClC-2Asp24 in adrenocortical cells increased expression of aldosterone synthase and aldosterone production. Our data indicate that CLCN2 mutations cause primary aldosteronism. They highlight the important role of chloride in aldosterone biosynthesis and identify ClC-2 as the foremost chloride conductor of resting glomerulosa cells.

Published
2018
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3. Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls

Author

Caterina Terrile, Juliette Bouchereau, Valeria Tiranti, Marina Paviolo, Paule Bénit, Manuel Schiff, Malgorzata Rak, Allan G. Rasmusson, Holger Prokisch, Arcangela Iuso, Thomas Schwarzmayr, Pierre Rustin, Alessia Catania, Laura S. Kremer, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Medical Genetics and Neurogenetics [Milan, Italy], Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institute of Human Genetics [Neuherberg] (IHG), Helmholtz-Zentrum München (HZM), Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Centre de référence pour les erreurs innées du métabolisme [Hôpital Robert Debré - APHP], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Biology [Lund, Sweden] (Biology building A), Lund University [Lund, Sweden], Department of Pediatrics [Munich, Germany] (Dr. von Hauner Children’s Hospital), Ludwig-Maximilians-Universität München (LMU), This study was supported by the German BMBF and Horizon2020 through E-Rare project GENOMIT (01GM1603 and 01GM1906B to H.P.), Horizon2020 Project SOUND (633974 to H.P.), German Network for Mitochondrial Disorders (mitoNET 01GM1113C to H.P.), AMMi (Association contre les Maladies Mitochondriales) grants to M.P., P.R., P.B. and M.S., E-Rare project GENOMIT (ANR-15-RAR3–0012 to P.R., A.C. and M.S.), Italian Ministry of Health (RF-2016-02361495 to A.C.), Mitocon (Grant no. 2018–01 to V.T.), Mariani Foundation (V.T.)., ANR-15-RAR3-0012,GENOMIT,Mitochondrial Disorders- from a pan-European Registry to medical genetics, toward molecular mechanisms and new therapeutic options(2015), European Project: 633974,H2020,H2020-PHC-2014-two-stage,SOUND(2015), Helmholtz Zentrum München = German Research Center for Environmental Health, Lund University [Lund], Rak, Malgorzata, Mitochondrial Disorders- from a pan-European Registry to medical genetics, toward molecular mechanisms and new therapeutic options - - GENOMIT2015 - ANR-15-RAR3-0012 - E-Rare-3 - VALID, and Statistical multi-Omics UNDerstanding of Patient Samples - SOUND - - H20202015-09-01 - 2018-08-31 - 633974 - VALID

Subjects
0301 basic medicine, Arabidopsis thaliana, [SDV]Life Sciences [q-bio], Arabidopsis, lcsh:Medicine, Mitochondrion, medicine.disease_cause, 0302 clinical medicine, NADH, NADPH Oxidoreductases, Pharmacology (medical), [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cells, Cultured, Genetics (clinical), chemistry.chemical_classification, biology, Chemistry, NADH dehydrogenase, Mitochondria, Mitochondrial Diseases, Complex I, Alternative Dehydrogenases, Arabidopsis Thaliana, Atnda2, General Medicine, AtNDA2, ddc, [SDV] Life Sciences [q-bio], Mitochondrial respiratory chain, Biochemistry, Saccharomyces cerevisiae Proteins, Saccharomyces cerevisiae, Mitochondrial diseases, Transfection, 03 medical and health sciences, Oxidoreductase, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Alternative dehydrogenases, Electron Transport Complex I, Arabidopsis Proteins, Superoxide Dismutase, Research, lcsh:R, NADPH Dehydrogenase, Fibroblasts, biology.organism_classification, Yeast, 030104 developmental biology, biology.protein, 030217 neurology & neurosurgery, Oxidative stress
Abstract

Background Complex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts. Results We showed that, other than ScNDI1, two different NDH-2 (AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells. Conclusions In conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.

Published
2019
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4. SMC2, encoding a core component of the condensin complex, is mutated in Hallermann-Streiff syndrome: a condensinopathy revelation

Author

Diab, Farah, Watrin, Erwan, Li, Yun, Yigit, Gökhan, Wollnik, Bernd, Couvet, Sandrine, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institute of Human Genetics [Neuherberg] (IHG), and Helmholtz Zentrum München = German Research Center for Environmental Health

Subjects
[SDV] Life Sciences [q-bio], [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Hallermann-Streiff Syndrome, SMC2, variant, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Abstract

Hallermann-Streiff syndrome (HSS) is a rare developmental disorder characterized by premature aging, congenital cataracts, microphthalmia, hypotrichosis, beaked nose, skin atrophy, micrognathia, dental anomalies and proportionate short stature. Only a minority of HSS patients show intellectual disability. Since its first description in the mid-50s no causative gene has been identified and therefore, the molecular basis of HSS is still unknown. Recently, however, whole-exome sequencing studies in parent-index trios and single cases have detected the first mutation underlying HSS in the SMC2 gene. SMC2 belongs to the family of the structural maintenance of chromosome proteins and forms a complex with SMC4 involved in sister chromatid condensation, mitotic chromosome integrity, gene expression, and DNA repair. To shed light into the molecular mechanisms underlying HSS, we performed gene expression profiling in cultured skin fibroblasts. Transcriptome analysis revealed marked alterations in the expression levels of several genes associated with chromosome segregation, mitotic nuclear division, cell cycle DNA replication and double-strand break repair. In addition, SMC2 mRNA expression revealed a significant down-regulation in patients’ cells correlating with the mutation. Furthermore, a significant reduction in SMC2 and SMC4 protein levels was observed in patients’ primary fibroblasts. As short telomeres are considered as a hallmark of aging, their length was assessed in HSS patients. Remarkably, patients’ cells showed telomere shortening. Our findings add for the first time new insights into the pathophysiology of HSS.

Published
2019

5. Replication of restless legs syndrome loci in three European populations

Author

Viola Gschliesser, Sona Nevsimalova, Alexander Zimprich, D. Roeske, Kaisa Silander, Thomas Meitinger, Birgit Högl, Birgit Frauscher, Christian Gieger, Werner Poewe, Heinz Erich Wichmann, Peter Lichtner, Olli Polo, Karel Sonka, Barbara Schormair, Juliane Winkelmann, Pavel Vodicka, Jana Vavrova, Bertram Müller-Myhsok, Leena Peltonen, David Kemlink, Laboratoire d'étude des maladies du cerveau, Université de Montréal (UdeM)-Hopital Notre-Dame-Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Sleep Research Unit, University of Turku, Department of Neurology, Innsbruck Medical University [Austria] (IMU), Medizinische Universität Wien = Medical University of Vienna, Institute of Human Genetics [Neuherberg] (IHG), Helmholtz-Zentrum München (HZM), Baylor College of Medecine, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Molecular Medicine and Therapeutics, University of British Columbia (UBC), Max Planck Institute of Psychiatry, and Max-Planck-Gesellschaft

Subjects
Male, MAP Kinase Kinase 5, 0302 clinical medicine, Gene Frequency, Odds Ratio, Genetic epidemiology, Myeloid Ecotropic Viral Integration Site 1 Protein, Genetics (clinical), Finland, Czech Republic, Genetics, 0303 health sciences, education.field_of_study, Middle Aged, Neoplasm Proteins, ddc, Neurology, Austria, Female, Co-Repressor Proteins, Adult, Genotype, Population, Single-nucleotide polymorphism, Locus (genetics), periodic limb movements, genetic risk-factor, susceptibility locus, linkage, association, heterogeneity, family, confirmation, expression, sleep, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Restless Legs Syndrome, mental disorders, Humans, Genetic Predisposition to Disease, education, Allele frequency, 030304 developmental biology, Genetic association, Association studies, Aged, Homeodomain Proteins, Odds ratio, body regions, Repressor Proteins, BTBD9, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Restless legs syndrome (RLS) is associated with common variants in three intronic and intergenic regions in MEIS1, BTBD9, and MAP2K5/LBXCOR1 on chromosomes 2p, 6p and 15q. Methods: Our study investigated these variants in 649 RLS patients and 1230 controls from the Czech Republic (290 cases and 450 controls), Austria (269 cases and 611 controls) and Finland (90 cases and 169 controls). Ten single nucleotide polymorphisms (SNPs) within the three genomic regions were selected according to the results of previous genome-wide scans. Samples were genotyped using Sequenom platforms. Results: We replicated associations for all loci in the combined samples set (rs2300478 in MEIS1, p=1.2661025, odds ratio (OR)=1.47, rs3923809 in BTBD9, p=4.1161025, OR=1.58 and rs6494696 in MAP2K5/LBXCOR1, p=0.04764, OR=1.27). Analysing only familial cases against all controls, all three loci were significantly associated. Using sporadic cases only, we could confirm the association only with BTBD9. Conclusion: Our study shows that variants in these three loci confer consistent disease risks in patients of European descent. Among the known loci, BTBD9 seems to be the most consistent in its effect on RLS across populations and is also most independent of familial clustering.

Published
2008
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