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.

GRIA1 编码 α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) 受体的 GluA1 亚基，AMPA 受体是配体门控离子通道，充当神经递质L-谷氨酸 (Glu) 的兴奋性受体。AMPA 受体 (AMPAR) 是具有四个亚基的同聚或异聚蛋白复合物，每个亚基由不同的基因GRIA1至GRIA4编码。尽管含有 GluA1 的 AMPAR 在大脑功能中起着至关重要的作用，但与有害GRIA1序列变体相关的人类表型尚未确定。具有从头错义和无意义GRIA1的受试者通过国际合作确定了变体。对受试者进行了详细的表型和遗传评估，并在体外评估了变异的致病性，以表征 AMPAR 功能和表达的变化。此外，建立了两个非洲爪蟾CRISPR-Cas9 F ₀模型来表征体内后果。七名具有罕见GRIA1的无关个体变体被识别。一个人携带纯合无义变体（p.Arg377Ter），六个人有杂合错义变体（p.Arg345Gln、p.Ala636Thr、p.Ile627Thr 和 p.Gly745Asp），其中 p.Ala636Thr 变体在三个人中反复出现. 该队列显示受试者患有复发性神经发育障碍，主要影响认知和言语。对携带GRIA1变异突变的主要含 GluA1 的 AMPAR 亚型的功能评估表明，四种错义变异中的三种严重扰乱了受体功能。纯合停止增益变体完全破坏了含有 GluA1 的 AMPAR 的表达。非洲爪蟾1模型显示瞬时运动缺陷、间歇性癫痫发作表型和突变体工作记忆的显着损害。这些数据支持由影响 AMPAR 功能的GRIA1中的杂合和纯合变异引起的发育障碍。