Identification and functional evaluation of GRIA1 missense and truncation variants in patients with ID: an emerging neurodevelopmental phenotype

Vardha Ismail, Linda Grønborg Dorvil, Annie Godwin, Mane Sahakian, Sian Ellard, Karen L. Stals, Katrina Tatton-Brown, Nicola C. Foulds, Gabrielle Wheway, Matthew Parker, Signe M. Lyngby, Miriam G. Pedersen, Julie Desir, Allan Bayat, Maria Musgaard, Matt Guille, Anders Skov Kristensen, Diana Baralle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Background: GRIA1 encodes the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4. Despite GluA1-containing AMPARs having a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. This study shows that mutations in GRIA1 cause both dominant and recessive neurodevelopmental disorders.

Methods: Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated using electrophysiological and biochemical analyses to characterize changes in AMPAR receptor function and expression. In addition, two Xenopus gria1 CRISPR/Cas9 F0 models were established and successfully used to characterize the in vivo consequences.

Results: Seven unrelated patients with rare GRIA1 variants were identified. One patient carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense mutations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, p.Gly745Asp) of which the p.Ala636Thr variant was recurrent in three patients. 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. In addition, data from the Xenopus 1 gria1 models shows transient motor deficits, an intermittent seizure phenotype and, by using a newly described method, a significant impairment to working memory in mutants.

Conclusion: These data support the first description of a new developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.
Original languageEnglish
Pages (from-to)1217-1241
JournalAmerican Journal of Human Genetics
Issue number7
Publication statusPublished - 7 Jul 2022


  • AMPA receptor
  • iGluR
  • glutamate receptor 1
  • GRIA1
  • neurodevelopmental impairment
  • Xenopus, free movement pattern Y maze
  • UKRI
  • MRC
  • MR/V012177/1
  • BB/K019988/1


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