Fiche publication
Date publication
juillet 2024
Journal
Communications biology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr KUENTZ Paul
Tous les auteurs :
Ghaffar A, Akhter T, Strømme P, Misceo D, Khan A, Frengen E, Umair M, Isidor B, Cogné B, Khan AA, Bruel AL, Sorlin A, Kuentz P, Chiaverini C, Innes AM, Zech M, Baláž M, Havrankova P, Jech R, Ahmed ZM, Riazuddin S, Riazuddin S
Lien Pubmed
Résumé
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.
Mots clés
Humans, Microcephaly, genetics, Intellectual Disability, genetics, Animals, Male, Female, Mice, Developmental Disabilities, genetics, HEK293 Cells, Zebrafish, genetics, Nerve Tissue Proteins, genetics, Child, Preschool, Chlorocebus aethiops, COS Cells, Child, Neurons, metabolism, Microtubule-Associated Proteins, genetics
Référence
Commun Biol. 2024 07 8;7(1):831
