Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome

Am J Hum Genet. 2022 Jul 7;109(7):1217-1241. doi: 10.1016/j.ajhg.2022.05.009.

Vardha Ismail ¹, Linda G Zachariassen ², Annie Godwin ³, Mane Sahakian ², Sian Ellard ⁴, Karen L Stals ⁵, Emma Baple ⁴, Kate Tatton Brown ⁶, Nicola Foulds ¹, Gabrielle Wheway ⁷, Matthew O Parker ⁸, Signe M Lyngby ², Miriam G Pedersen ², Julie Desir ⁹, Allan Bayat ¹⁰, Maria Musgaard ¹¹, Matthew Guille ³, Anders S Kristensen ¹², Diana Baralle ¹³

Affiliations

1 Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Coxford Rd, Southampton SO165YA, UK.
2 Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
3 European Xenopus Resource Centre, School of Biological Sciences, King Henry Building, King Henry I Street, Portsmouth PO1 2DY, UK.
4 Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK; University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK.
5 Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK.
6 South-West Thames Clinical Genetics Service, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
7 Faculty of Medicine, University of Southampton, Duthie Building, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
8 School of Pharmacy and Biomedical Sciences, University of Portsmouth, Old St Michael's Building, White Swan Road, Portsmouth PO1 2DT, UK.
9 Département de Génétique Clinique - Institut de Pathologie et de Génétique, Institut de Pathologie et de Génétique, Avenue Georges Lemaître, 25 6041 Gosselies, Belgium.
10 Danish Epilepsy Centre, Department of Epilepsy Genetics and Personalized Medicine, 4293 Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark.
11 Department of Chemistry and Biomolecular Sciences, University of Ottawa, 75 Laurier Ave E, Ottawa, ON K1N 6N5, Canada.
12 Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: [email protected].
13 Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Coxford Rd, Southampton SO165YA, UK; Faculty of Medicine, University of Southampton, Duthie Building, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. Electronic address: [email protected].

PMID: 35675825 DOI: 10.1016/j.ajhg.2022.05.009

Abstract

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. Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. 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 in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F₀ 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.

Keywords

AMPA receptor; CRISPR; GRIA1; Xenopus, free movement pattern Y maze; glutamate receptor 1; iGluR; neurodevelopmental impairment.

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