SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance.

Autor:	Cordovado A; UMR 1253, iBrain, University of Tours, INSERM, Tours 37032, France., Schaettin M; Department of Molecular Life Sciences, Neuroscience Center Zurich, University of Zurich, Zurich 8057, Switzerland., Jeanne M; UMR 1253, iBrain, University of Tours, INSERM, Tours 37032, France.; Genetics Department, University Hospital of Tours, Tours 37044, France., Panasenkava V; UMR 1253, iBrain, University of Tours, INSERM, Tours 37032, France., Denommé-Pichon AS; Functional Unit in Innovative Genomic Diagnosis of Rare Diseases, FHU-TRANSLAD, Dijon-Bourgogne University Hospital, Dijon 21079, France.; UMR1231 GAD, INSERM - Bourgogne-Franche Comté University, Dijon 21000, France., Keren B; Genetics Department, Pitié-Salpêtrière Hospital, AP-HP. Sorbonne University, Paris 75651, France., Mignot C; Genetics Department, Pitié-Salpêtrière Hospital, AP-HP. Sorbonne University, Paris 75651, France., Doco-Fenzy M; University Hospital Reims, AMH2, Genetics Division, SFR CAP santé EA3801, Reims 51100, France., Rodan L; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA., Ramsey K; Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ 85012, USA., Narayanan V; Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ 85012, USA., Jones JR; Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA., Prijoles EJ; Greenwood Genetic Center, Greenwood, SC 29646, USA., Mitchell WG; Neurology Division, Keck School of Medicine, University of Southern California, Children's Hospital Los Angeles, CA 90027, USA., Ozmore JR; Dartmouth Hitchcock Medical Center, Lebanon, NH 03766, USA., Juliette K; Neurology Department, Gillette Children's Specialty Healthcare, St Paul, MN 55101, USA., Torti E; GeneDx, Gaithersburg, MD 20877, USA., Normand EA; GeneDx, Gaithersburg, MD 20877, USA., Granger L; Genetics Division, Department of Pediatric Development and Rehabilitation, Randall Children's Hospital, Portland, OR 97227, USA., Petersen AK; Genetics Division, Department of Pediatric Development and Rehabilitation, Randall Children's Hospital, Portland, OR 97227, USA., Au MG; Department of Genetics and Metabolism, University of Kentucky, Lexington, KY 40536, USA., Matheny JP; Department of Genetics and Metabolism, University of Kentucky, Lexington, KY 40536, USA., Phornphutkul C; Division of Human Genetics, Department of Pediatrics, Warren Alpert Medical School of Brown University, Hasbro Children's Hospital, Providence, RI 02903, USA., Chambers MK; Division of Genetics, Rhode Island Hospital, Hasbro Children's Hospital, Providence, RI 02903, USA., Fernández-Ramos JA; Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofía, IMIBIC and CIBERER, Córdoba 14004, Spain., López-Laso E; Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofía, IMIBIC and CIBERER, Córdoba 14004, Spain., Kruer MC; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA., Bakhtiari S; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA., Zollino M; Università Cattolica Sacro Cuore, Dipartimento Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Roma 00168, Italy.; Fondazione Policlinico A. Gemelli IRCCS, U. O. C. Genetica Medica, Roma 00168, Italy., Morleo M; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples 80078, Italy.; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples 80138, Italy., Marangi G; Università Cattolica Sacro Cuore, Dipartimento Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Roma 00168, Italy.; Fondazione Policlinico A. Gemelli IRCCS, U. O. C. Genetica Medica, Roma 00168, Italy., Mei D; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, Member of ERN Epicare, University of Florence, Florence 50139, Italy., Pisano T; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, Member of ERN Epicare, University of Florence, Florence 50139, Italy., Guerrini R; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, Member of ERN Epicare, University of Florence, Florence 50139, Italy., Louie RJ; Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA., Childers A; Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA., Everman DB; Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA., Isidor B; Medical Genetics Service, Clinical Genetics Unit, University Hospital of Nantes, Hôtel Dieu, Nantes 44093, France., Audebert-Bellanger S; Clinical Genetics Service, University Hospital of Brest, Morvan Hospital, Brest 29609, France., Odent S; Clinical Genetics Service, University Hospital, Genetic and Development Institute of Rennes IGDR, UMR 6290 University of Rennes, ITHACA ERN, Rennes 35203, France., Bonneau D; Department of Medical Genetics, University Hospital of Angers and Mitovasc INSERM 1083, CNRS 6015, Angers 49000, France., Gilbert-Dussardier B; Medical Genetics, University Hospital, La Milétrie, BP 577, Poitiers 86021, France., Redon R; INSERM, CNRS, UNIV Nantes, Thorax Institute, Nantes 44007, France., Bézieau S; INSERM, CNRS, UNIV Nantes, Thorax Institute, Nantes 44007, France.; Medical Genetics Service, University Hospital of Nantes, Nantes 44093, France., Laumonnier F; UMR 1253, iBrain, University of Tours, INSERM, Tours 37032, France., Stoeckli ET; Department of Molecular Life Sciences, Neuroscience Center Zurich, University of Zurich, Zurich 8057, Switzerland., Toutain A; UMR 1253, iBrain, University of Tours, INSERM, Tours 37032, France.; Genetics Department, University Hospital of Tours, Tours 37044, France., Vuillaume ML; UMR 1253, iBrain, University of Tours, INSERM, Tours 37032, France.; Genetics Department, University Hospital of Tours, Tours 37044, France.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2022 Sep 29; Vol. 31 (19), pp. 3325-3340.
DOI:	10.1093/hmg/ddac114
Abstrakt:	Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes. (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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