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Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development
Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 ( NAV2 ) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within t...
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Published in: | Cerebellum (London, England) England), 2023-04, Vol.22 (2), p.206-222 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (
NAV2
) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of
Nav2
in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the
NAV2
gene in human disease phenotypes. In this study, we identified a female affected with neurodevelopmental impairment and a complex brain and cardiac malformations in which clinical exome sequencing led to the identification of
NAV2
biallelic truncating variants. Through protein expression analysis and cell migration assay in patient-derived fibroblasts, we provide evidence linking NAV2 deficiency to cellular migration deficits. In model organisms, the overall CNS histopathology of the
Nav2
hypomorphic mouse revealed developmental anomalies including cerebellar hypoplasia and dysplasia, corpus callosum hypo-dysgenesis, and agenesis of the olfactory bulbs. Lastly, we show that the
NAV2
ortholog in
Drosophila
,
sickie
(
sick
) is widely expressed in the fly brain, and
sick
mutants are mostly lethal with surviving escapers showing neurobehavioral phenotypes. In summary, our results unveil a novel human neurodevelopmental disorder due to genetic loss of
NAV2
, highlighting a critical conserved role of the
NAV2
gene in brain and cerebellar development across species. |
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ISSN: | 1473-4230 1473-4222 1473-4230 |
DOI: | 10.1007/s12311-022-01379-3 |