A recurrent missense variant in the GRIA1 gene (p.Ala636Thr) was originally reported as de novo variants in patients with developmental delay/intellectual disability (De Ligt et al., 2012) and ASD (De Rubeis et al., 2014); the same variant was subsequently identified in three additional patients with a primary diagnosis of ASD (de novo in one case, unknown inheritance in the other two) in Geisheker et al., 2017. The p.Ala636Thr variant was not observed in over 60,000 individuals in ExAC (compared to being observed in 5 NDD cases, three of which were de novo; P=5.39E-03, one-tailed binomial test, genome-wide correction), and functional analysis of this variant using whole-cell voltage-clamp recordings of transfected HEK293 cells demonstrated a gain-of-function effect. Ismail et al., 2022 reported seven unrelated individuals with rare GRIA1 variants presenting with a neurodevelopmental syndrome characterized by intellectual disability, language impairment, and behavioral abnormalities (including autism spectrum disorder in three individuals); subsequent functional assessment of GRIA1 variants in this study showed that three of the four missense variants significantly disrupted receptor function, whereas a homozygous nonsense variant completely abolished expression of GluA1-containing AMPARs.
Molecular Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
