Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development

Area of Science:

• Neurogenetics
• Developmental Biology
• Human Genetics

Background:

• Cerebellar hypoplasia and dysplasia are heterogeneous disorders linked to neurodevelopmental impairment.
• The NAV2 gene is crucial for cytoskeletal dynamics and neurite outgrowth, particularly in the developing cerebellum.
• Previous studies in mice showed Nav2 deficiency causes cerebellar hypoplasia, but its role in human disease was unknown.

Purpose of the Study:

• To investigate the role of the NAV2 gene in human neurodevelopmental disorders.
• To characterize the cellular and organismal consequences of NAV2 deficiency.

Main Methods:

• Clinical exome sequencing identified biallelic NAV2 truncating variants in an affected individual.
• Protein expression and cell migration assays were performed on patient-derived fibroblasts.
• Analysis of Nav2 hypomorphic mouse models and Drosophila sickie mutants.

Main Results:

• NAV2 deficiency was linked to neurodevelopmental impairment, brain malformations (cerebellar hypoplasia/dysplasia, corpus callosum hypo-dysgenesis, olfactory bulb agenesis), and cardiac defects.
• Patient-derived fibroblasts showed impaired cellular migration.
• Nav2 deficiency in mice and Drosophila resulted in significant central nervous system developmental anomalies and neurobehavioral phenotypes.

Conclusions:

• This study identifies a novel human neurodevelopmental disorder caused by genetic loss of NAV2.
• NAV2 plays a critical, conserved role in brain and cerebellar development across species.
• NAV2 deficiency leads to cellular migration deficits and complex malformations.