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Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly
A. Ghaffar, T. Akhter, P. Strømme, D. Misceo, A. Khan, E. Frengen, M. Umair, B. Isidor, B. Cogné, AA. Khan, AL. Bruel, A. Sorlin, P. Kuentz, C. Chiaverini, AM. Innes, M. Zech, M. Baláž, P. Havrankova, R. Jech, ZM. Ahmed, S. Riazuddin, S. Riazuddin
Language English Country England, Great Britain
Document type Journal Article
Grant support
R01 NS107428
NINDS NIH HHS - United States
R01NS107428
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
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- MeSH
- Chlorocebus aethiops MeSH
- COS Cells MeSH
- Zebrafish genetics MeSH
- Child MeSH
- HEK293 Cells MeSH
- Humans MeSH
- Intellectual Disability * genetics MeSH
- Microcephaly * genetics pathology MeSH
- Mice MeSH
- Neurons metabolism pathology MeSH
- Child, Preschool MeSH
- Microtubule-Associated Proteins genetics metabolism MeSH
- Nerve Tissue Proteins genetics metabolism MeSH
- Developmental Disabilities * genetics MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Child, Preschool MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.
Alexander von Humboldt Fellowship Foundation Berlin 10117 Germany
Centre of Excellence in Molecular Biology University of the Punjab Lahore Pakistan
Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway
Department of Medical Genetics University of Calgary Calgary Alberta Canada
Department of Pediatrics CHU de Nice Fondation Lenval Nice France
Institute for Medical Genetics and Applied Genomics University of Tübingen Tübinge 72076 Germany
Institute of Human Genetics Technical University of Munich School of Medicine Munich Germany
Institute of Neurogenomics Helmholtz Munich Neuherberg Germany
Nantes Université CHU Nantes Service de Génétique Médicale 44000 Nantes France
National Center of Genetics 1 rue Louis Rech L 3555 Dudelange Luxembourg
References provided by Crossref.org
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