Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.

Autor:	Kurolap A; The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; The Genetics Institute, Rambam Health Care Campus, Haifa 3525408, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525428, Israel., Kreuder F; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC 3800, Australia., Gonzaga-Jauregui C; Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA., Duvdevani MP; Department of Genetics, Hadassah Medical Center, Jerusalem 91120, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel., Harel T; Department of Genetics, Hadassah Medical Center, Jerusalem 91120, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel., Tammer L; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel., Xin B; DDC Clinic - Center for Special Needs Children, Middlefield, OH 44062, USA., Bakhtiari S; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85013, USA; Departments of Child Health, Neurology, and Cellular and Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA., Rice J; Paediatric Rehabilitation, Women's and Children's Hospital, Adelaide, SA 5006, Australia., van Eyk CL; Paediatric Rehabilitation, Women's and Children's Hospital, Adelaide, SA 5006, Australia., Gecz J; Paediatric Rehabilitation, Women's and Children's Hospital, Adelaide, SA 5006, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia., Mah JK; Department of Pediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada., Atkinson D; Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen 2000, Belgium., Cope H; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Sullivan JA; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Douek AM; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC 3800, Australia., Colquhoun D; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC 3800, Australia., Henry J; School of Science, RMIT University, Melbourne, VIC 3000, Australia., Wlodkowic D; School of Science, RMIT University, Melbourne, VIC 3000, Australia., Parman Y; Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey., Candayan A; Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul 34342, Turkey., Kocasoy-Orhan E; Pediatric Radiology Unit, Rambam Health Care Campus, Haifa 3525408, Israel., Ilivitzki A; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525428, Israel; Pediatric Radiology Unit, Rambam Health Care Campus, Haifa 3525408, Israel., Soudry S; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525428, Israel; Department of Ophthalmology, Rambam Healthcare Campus, Haifa 3525408, Israel., Leibu R; Department of Ophthalmology, Rambam Healthcare Campus, Haifa 3525408, Israel., Glaser F; The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion - Israel Institute of Technology, Haifa 3200003, Israel., Sency V; DDC Clinic - Center for Special Needs Children, Middlefield, OH 44062, USA., Ast G; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel., Shashi V; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Fahey MC; Department of Pediatrics, Monash University, Melbourne, VIC 3800, Australia., Battaloğlu E; Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul 34342, Turkey., Jordanova A; Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen 2000, Belgium; Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia 1431, Bulgaria., Meiner V; Department of Genetics, Hadassah Medical Center, Jerusalem 91120, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel., Innes AM; Department of Pediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada., Wang H; DDC Clinic - Center for Special Needs Children, Middlefield, OH 44062, USA., Elpeleg O; Department of Genetics, Hadassah Medical Center, Jerusalem 91120, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel., Kruer MC; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85013, USA; Departments of Child Health, Neurology, and Cellular and Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA., Kaslin J; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC 3800, Australia., Baris Feldman H; The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; The Genetics Institute, Rambam Health Care Campus, Haifa 3525408, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525428, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address: hagitbf@tlvmc.gov.il.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2022 Mar 03; Vol. 109 (3), pp. 518-532. Date of Electronic Publication: 2022 Feb 01.
DOI:	10.1016/j.ajhg.2022.01.004
Abstrakt:	Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcama Δ mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcama Δ mutants displayed a trend toward increased amounts of α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system. Competing Interests: Declaration of interests C.G.-J. is a full-time employee of the Regeneron Genetics Center and receives stock options as part of compensation. All other authors have no conflicts to declare. (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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