Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity
| Autor: | Alina Kurolap, Florian Kreuder, Claudia Gonzaga-Jauregui, Morasha Plesser Duvdevani, Tamar Harel, Luna Tammer, Baozhong Xin, Somayeh Bakhtiari, James Rice, Clare L. van Eyk, Jozef Gecz, Jean K. Mah, Derek Atkinson, Heidi Cope, Jennifer A. Sullivan, Alon M. Douek, Daniel Colquhoun, Jason Henry, Donald Wlodkowic, Yesim Parman, Ayşe Candayan, Elif Kocasoy-Orhan, Anat Ilivitzki, Shiri Soudry, Rina Leibu, Fabian Glaser, Valerie Sency, Gil Ast, Vandana Shashi, Michael C. Fahey, Esra Battaloğlu, Albena Jordanova, Vardiella Meiner, A. Micheil Innes, Heng Wang, Orly Elpeleg, Michael C. Kruer, Jan Kaslin, Hagit Baris Feldman |
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| Přispěvatelé: | Undiagnosed Diseases Network |
| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Am J Hum Genet The American journal of human genetics |
| ISSN: | 1537-6605 0002-9297 |
| Popis: | 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(Delta) 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(Delta) mutants displayed a trend toward increased amounts of alpha-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. |
| Databáze: | OpenAIRE |
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