Relevance to Autism

Analysis of whole-exome sequencing data from 13,091 individuals diagnosed with autism recruited from the SSC, SPARK, and iPSYCH cohorts, 19,488 first-degree relatives of individuals with autism from the SSC and SPARK cohorts, and 194,070 individuals identified from unselected population samples from the iPSYCH and UK Biobank cohorts in Rolland et al., 2023 identified CACNG2 as a novel ASD candidate gene intolerant to loss-of-function variants with an odds ratio greater than 10. Several de novo variants in the CACNG2 gene, including two de novo missense variants and a de novo intragenic deletion that was predicted to result in an in-frame deletion of 30 amino acids from the extracellular AMPA receptor-binding domain, have been identified in ASD probands (Brandler et al., 2016; Lim et al., 2017; Yuan et al., 2023). A de novo missense variant in the CACNG2 gene (p.Val143Leu) was identified in a patient presenting with sporadic non-syndromic intellectual disability in Hamdan et al., 2011; this variant was experimentally demonstrated to result in reduced binding to GluR1 or GluR2 AMPAR subunits, reduced GluR1 cell surface expression, and reduced miniEPSC amplitude and frequency in transfected hippocampal neurons. Subsequent characterization of a knock-in mouse with the p.Val143Leu variant in Caldeira et al., 2022 demonstrated that these mice displayed cognitive and social deficits, as well as hippocampal synaptic transmission defects.

Molecular Function

The protein encoded by this gene is a type I transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. The AMPA subtype of ionotropic glutamate receptors are ligand gated ion channels that are typically activated by glutamate released from presynaptic neuron terminals and mediate fast neurotransmission in excitatory synapses. TARPs thus play an important role in synaptic plasticity, learning and memory.

External Links

References