Autism-associated ARHGEF9 variants impair GABAergic synapses and ultrasonic communication by reducing gephyrin phosphorylation.

ABSTRACT: Missense and truncating variants of the X-chromosome-linked ARHGEF9 gene encoding collybistin (Cb) cause intellectual disability and epilepsy. Here we report novel rare variants in ARHGEF9 identified via exome sequencing in male individuals with autism spectrum disorders (ASD). Functional analyses revealed that p.R290C promotes abnormal gephyrin clustering in COS-7 cells and reduces inhibitory synapse density in cultured hippocampal neurons. Electrophysiological recordings revealed that p.V374F and p.G485S, in conjunction with p.R290C, induce defective inhibitory synaptic transmission. Furthermore, only the p.G485S markedly decreased phosphatidylinositol 3-phosphate-binding activity. Mice with conditional knockout (cKO) of Cb displayed altered inhibitory synaptic density and transmission i

SUBMITTER: Jung H 

PROVIDER: S-EPMC12916317 | biostudies-literature | 2026 Mar

REPOSITORIES: biostudies-literature