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KATNAL2 mutation cause hydrocephalus by impairing vesicular trafficking and ependymal cell polarity in ASD

ABSTRACT: Autism spectrum disorders (ASD) are characterized by intricate neurodevelopmental abnormalities, yet the molecular underpinnings remain elusive for many high-risk genes, including KATNAL2. Here, we identify KATNAL2 as a key regulator of the intracellular vesicular system in the ependymal epithelium, crucial for vesicle trafficking and ciliary function. We demonstrate that an ASD-associated mutation in KATNAL2 disrupts its molecular activity, impairing intracellular vesicle trafficking, which in turn alters planar cell polarity and ciliary motion in ependymal cells. These defects lead to compromised cerebrospinal fluid circulation and postnatal hydrocephalus in mice. Notably, ependymal-specific ablation of Katnal2 in neonatal mice recapitulated the hydrocephalic phenotype. Our findings uncover a previously unrecognized molecular role for the ASD risk gene KATNAL2 in ependymal cells, underscoring its essential function in vesicle trafficking and cell polarity regulation, and suggest new avenues for targeted therapeutic strategies for ASD.

ORGANISM(S): Mus musculus

PROVIDER: GSE278728 | GEO | 2025/05/01

REPOSITORIES: GEO

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