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 F
0
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.