PUBLICATION
Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity
- Authors
- Kurolap, A., Kreuder, F., Gonzaga-Jauregui, C., Duvdevani, M.P., Harel, T., Tammer, L., Xin, B., Bakhtiari, S., Rice, J., van Eyk, C.L., Gecz, J., Mah, J.K., Atkinson, D., Cope, H., Sullivan, J.A., Douek, A.M., Colquhoun, D., Henry, J., Wlodkowic, D., Parman, Y., Candayan, A., Kocasoy-Orhan, E., Ilivitzki, A., Soudry, S., Leibu, R., Glaser, F., Sency, V., Undiagnosed Diseases Network, Ast, G., Shashi, V., Fahey, M.C., Battaloğlu, E., Jordanova, A., Meiner, V., Innes, A.M., Wang, H., Elpeleg, O., Kruer, M.C., Kaslin, J., Baris Feldman, H.
- ID
- ZDB-PUB-220203-10
- Date
- 2022
- Source
- American journal of human genetics 109(3): 518-532 (Journal)
- Registered Authors
- Douek, Alon M., Kaslin, Jan
- Keywords
- NRCAM, hypotonia, neurodevelopmental disease, neuronal cell adhesion molecule, peripheral neuropathy, spasticity
- MeSH Terms
-
- Animals
- Axons/metabolism
- Cell Adhesion/genetics
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/metabolism
- Cell Adhesion Molecules, Neuronal
- Humans
- Mice
- Muscle Hypotonia/genetics
- Muscle Hypotonia/metabolism
- Muscle Spasticity/metabolism
- Neurodevelopmental Disorders*/genetics
- Neurodevelopmental Disorders*/metabolism
- Peripheral Nervous System Diseases*
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 35108495 Full text @ Am. J. Hum. Genet.
Citation
Kurolap, A., Kreuder, F., Gonzaga-Jauregui, C., Duvdevani, M.P., Harel, T., Tammer, L., Xin, B., Bakhtiari, S., Rice, J., van Eyk, C.L., Gecz, J., Mah, J.K., Atkinson, D., Cope, H., Sullivan, J.A., Douek, A.M., Colquhoun, D., Henry, J., Wlodkowic, D., Parman, Y., Candayan, A., Kocasoy-Orhan, E., Ilivitzki, A., Soudry, S., Leibu, R., Glaser, F., Sency, V., Undiagnosed Diseases Network, Ast, G., Shashi, V., Fahey, M.C., Battaloğlu, E., Jordanova, A., Meiner, V., Innes, A.M., Wang, H., Elpeleg, O., Kruer, M.C., Kaslin, J., Baris Feldman, H. (2022) Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity. American journal of human genetics. 109(3):518-532.
Abstract
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 nrcamaΔ 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, nrcamaΔ 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping