Relevance to Autism

Duncan et al., 2021 reported nine variants in the CLCN3 gene in eleven individuals with global developmental delay/intellectual disability and neurodevlopmental disorders of varying severity; mood or behavioral disorders were frequently observed in affected individuals, and four of these patients were reported to present with autism. Two of the de novo missense variants in CLCN3 identified in this report (p.Ile607Thr and p.Thr570Ile) were experimentally shown to have increased currents at negative cytoplasmic voltage and loss of inhibition by luminal acidic pH; one of the individuals with autism in this cohort had the p.Thr570Ile variant. A de novo missense variant in CLCN3 had previously been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Molecular Function

This gene encodes a member of the voltage-gated chloride channel (ClC) family. The encoded protein is present in all cell types and localized in plasma membranes and in intracellular vesicles. It is a multi-pass membrane protein which contains a ClC domain and two additional C-terminal CBS (cystathionine beta-synthase) domains. The ClC domain catalyzes the selective flow of Cl- ions across cell membranes, and the CBS domain may have a regulatory function. This protein plays a role in both acidification and transmitter loading of GABAergic synaptic vesicles, and in smooth muscle cell activation and neointima formation. This protein is required for lysophosphatidic acid (LPA)-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. The protein activity is regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in glioma cells.

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