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1. Compound heterozygous mutations in the LOXL4 gene: a novel cause of contractural myopathy

Author

Enzo Cohen, Isabelle Nelson, Corine Gartioux, Maud Beuvin, Zaineb Mezdari, Fanny Roth, Rabah Ben Yaou, Susana Quijano-Roy, Tanya Stojkovic, Robert-Yves Carlier, Valérie Allamand, Gisèle Bonne, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Service de Pédiatrie, Rééducation et Réanimation Neurorespiratoire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Myologie, 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Imagerie Médicale [Raymond-Poincaré], Hôpital Raymond Poincaré [AP-HP], and Bonne, Gisèle

Subjects
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, rare neuromuscular diseases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Abstract

Communication Orale; International audience

Published
2019

2. Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations

Author

Merih Berberoğlu, Régis Coutant, Şenay Savaş Erdeve, Cécile Brachet, Caroline Thalassinos, Frédéric Brioude, Michel Polak, Erdal Kurnaz, Sabrina Belkacem, Claudine Heinrichs, Aude Soleyan, Zeynep Şıklar, Nathalie Collot, Philippe Chanson, Jean-Claude Carel, Zehra Aycan, Marie-Laure Sobrier, Serge Amselem, Géraldine Viot, Noureddine Kaffel, Stanislas Lyonnet, Philippe Duquesnoy, Eliane Khallouf, Marie Legendre, Enzo Cohen, Soumeya Fedala, Sophie Rose, Florence Dastot, Frédérique Gatelais, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lamine Debaghine [Alger, Algérie] (HLD), Centre Hospitalier Universitaire Bab El Oued [Alger, Algérie] (CHU Bab El Oued), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Hôtel-Dieu de France (HDF), Université Saint-Joseph de Beyrouth (USJ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpitaux Universitaires Paris Centre (CHU Paris Centre), Hôpital Robert Debré, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Universitaire des Enfants Reine Fabiola [Brussels, Belgium]. (HUERF), Complexe Médical Multidisciplinaire [Sfax, Tunisia] (C2M), Ankara University School of Medicine [Turkey], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Dupuis, Christine, 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), Physiopathologie des maladies génétiques d'expression pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Service de Génétique [Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Universitaire des Enfants Reine Fabiola, Université libre de Bruxelles (ULB), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Division of Paediatric Endocrinology, Dr Sami Ulus Woman Health, Children Research Hospital, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [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), Children's University Hospital Queen Fabiola [Bruxelles, Belgium], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Receptors, Neuropeptide, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, MESH: Amino Acid Sequence, medicine.disease_cause, molecular epidemiology, MESH: Genotype, Exon, Receptors, Pituitary Hormone-Regulating Hormone, Cyclic AMP, IGHD, MESH: Human Growth Hormone, Missense mutation, MESH: DNA Mutational Analysis, Idiopathic Isolated Growth Hormone Deficiency, Genetics (clinical), genotype‐phenotype correlation, MESH: Cyclic AMP, MESH: Genetic Association Studies, Genetics, 0303 health sciences, Mutation, Human Growth Hormone, MESH: Receptors, Neuropeptide, 030305 genetics & heredity, MESH: Genetic Predisposition to Disease, MESH: Amino Acid Substitution, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], functional studies, Female, MESH: Mutation, Genotype, MESH: Pedigree, Genetic counseling, GHRHR, Biology, genotype-phenotype correlation, MESH: Dwarfism, Pituitary, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Dwarfism, Pituitary, Gene, Alleles, Genetic Association Studies, 030304 developmental biology, MESH: Humans, Molecular epidemiology, MESH: Receptors, Pituitary Hormone-Regulating Hormone, MESH: Alleles, MESH: Male, Amino Acid Substitution, MESH: Female
Abstract

International audience; Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.

Published
2019
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3. Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients

Author

Michel Polak, Enzo Cohen, Sophie Rose, Frédéric Brioude, Nathalie Collot, Daniela Larizza, Marie Legendre, Florence Dastot, Juliane Léger, Anne Marie Bertrand, Philippe Duquesnoy, Marie Laure Sobrier, Philippe Touraine, Mohamad Maghnie, Bruno Copin, Maïté Tauber, Irène Netchine, Serge Amselem, Isabelle Oliver-Petit, Laura González Briceño, Thomas Edouard, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Genova = University of Genoa (UniGe), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], 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 Chirurgie Digestive et Endocrinienne [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'explorations fonctionnelles [CHU Trousseau], Fondazione IRCCS Policlinico San Matteo [Pavia], Università degli Studi di Pavia = University of Pavia (UNIPV), Couvet, Sandrine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], and Societe Francaise d'Endocrinologie et Diabetologie PediatriqueFondation pour la Recherche Medicale PLP20131028838

Subjects
0301 basic medicine, Male, Pituitary gland, MESH: Sequence Homology, Amino Acid, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Sequence Homology, Hypopituitarism, MESH: Amino Acid Sequence, medicine.disease_cause, MESH: Hypopituitarism, Biochemistry, Cohort Studies, 0302 clinical medicine, Endocrinology, MESH: Child, Child, MESH: Cohort Studies, Genetics, Sanger sequencing, Mutation, Blotting, MESH: Infant, Newborn, MESH: Transcription Factors, MESH: Follow-Up Studies, Prognosis, MESH: Infant, Ectopic Posterior Pituitary, Pedigree, Diabetes and Metabolism, [SDV] Life Sciences [q-bio], Amino Acid, medicine.anatomical_structure, Sella turcica, Child, Preschool, symbols, Female, Western, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Pedigree, Blotting, Western, LIM-Homeodomain Proteins, 030209 endocrinology & metabolism, Context (language use), Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Prognosis, 03 medical and health sciences, symbols.namesake, Internal medicine, medicine, Humans, Immunoprecipitation, MESH: Blotting, Western, Amino Acid Sequence, Preschool, Biomarkers, Follow-Up Studies, Infant, Infant, Newborn, Sequence Homology, Amino Acid, Transcription Factors, Biochemistry (medical), MESH: Adolescent, MESH: LIM-Homeodomain Proteins, MESH: Humans, MESH: Immunoprecipitation, MESH: Child, Preschool, Heterozygote advantage, medicine.disease, Newborn, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Biomarkers, MESH: Female
Abstract

Context:LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism.Objective:The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4.Design and Patients:We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants.Results:We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant.Conclusion:This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.

Published
2017
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