Relevance to Autism

A maternally-inherited missense variant in the GLRA2 gene was identified in a female ASD proband in Piton et al., 2011; subsequent functional analysis of this variant in Zhang et al., 2017 demonstrated properties consistent with an overall gain-of-function effect, such as reduced glycine sensitivity and significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. De novo missense variants in this gene have also been identified in individuals with ASD (Iossifov et al., 2012; Iossifov et al., 2014; Pilorge et al., 2016). Pilorge et al., 2016 demonstrated that two of these missense variants resulted in impaired surface expression and reduced sensitivity to glycine; in the same report, a maternally-inherited 151 kb microdeletion affecting the GLRA2 gene that was identified in a male patient with non-syndromic autism was shown to impair cell membrane localization and resulted in failure to rescue axon-branching defects in spinal motor axons in zebrafish with targeted glra2 knockdown. Functional analysis of the ASD-associated p.Asn136Ser missense variant, which was originally identified in an SSC proband, in Drosophila in Marcogliese et al., 2022 demonstrated a loss-of-function effect (mutant flies were capable of copulating within trial period similar to TG4 mutant alone, compared to a failure to copulate observed in humanized reference flies; failure to reduce expected viability to the extent of corresponding reference allele upon ubiquitous overexpression; electroretinogram recordings on fly eyes expressing human GLRA2 demonstrated that expression of mutant GLRA2 in pre-synaptic photoreceptors resulted in a decrease in amplitude of "OFF" transients, indicating a decrease in synaptic tranmission). Marcogliese et al., 2022 also characterized 13 unrelated individuals with GLRA2 missense variants (8 females with de novo variants and 5 males with maternally-inherited variants); all 13 individuals presented with developmental delay/intellectual disability, and autism spectrum disorder was reported in four (one female, three males).

Molecular Function

A ligand-gated channel mediating a chloride-dependent inhibitory neurotransmission

External Links

References

Model Summary

Glra2 knockout mice did not show any electrophysiological responses to glycine.

References