PUBLICATION
Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly
- Authors
- Ghaffar, A., Akhter, T., Strømme, P., Misceo, D., Khan, A., Frengen, E., Umair, M., Isidor, B., Cogné, B., Khan, A.A., Bruel, A.L., Sorlin, A., Kuentz, P., Chiaverini, C., Innes, A.M., Zech, M., Baláž, M., Havrankova, P., Jech, R., Ahmed, Z.M., Riazuddin, S., Riazuddin, S.
- ID
- ZDB-PUB-240709-18
- Date
- 2024
- Source
- Communications biology 7: 831831 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Intellectual Disability*/genetics
- Child
- Humans
- Microcephaly*/genetics
- Microcephaly*/pathology
- Microtubule-Associated Proteins/genetics
- Microtubule-Associated Proteins/metabolism
- COS Cells
- HEK293 Cells
- Mice
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Zebrafish/genetics
- Neurons/metabolism
- Neurons/pathology
- Male
- Chlorocebus aethiops
- Developmental Disabilities*/genetics
- Child, Preschool
- Female
- PubMed
- 38977784 Full text @ Commun Biol
Citation
Ghaffar, A., Akhter, T., Strømme, P., Misceo, D., Khan, A., Frengen, E., Umair, M., Isidor, B., Cogné, B., Khan, A.A., Bruel, A.L., Sorlin, A., Kuentz, P., Chiaverini, C., Innes, A.M., Zech, M., Baláž, M., Havrankova, P., Jech, R., Ahmed, Z.M., Riazuddin, S., Riazuddin, S. (2024) Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly. Communications biology. 7:831831.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping