Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome
Vardha Ismail, Linda G. Zachariassen, Annie Godwin, Mane Sahakian, Sian Ellard, Karen Stals, Emma L. Baple, Kate Tatton Brown, Nicola Foulds, Gabrielle Wheway, Matthew O. Parker, Signe Meisner Lyngby, Miriam G. Pedersen, Julie Désir, Allan Bayat, Maria Musgaard, Matthew Guille, Anders S. Kristensen, Diana Baralle
Abstract
models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.