Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome.
Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome.
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DOI：
10.1016/j.ajhg.2022.05.009
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发表时间：
2022-07-07
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
GRIA 1编码α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）受体的GluA 1亚基，AMPA受体是作为神经递质L-谷氨酸（Glu）兴奋性受体的配体门控离子通道。AMPA受体（AMPAR）是具有四个亚基的同源或异源蛋白质复合物，每个亚基由不同的基因GRIA 1至GRIA 4编码。虽然含有GluA 1的AMPAR在脑功能中具有至关重要的作用，但与有害的GRIA 1序列变体相关的人类表型尚未建立。通过国际合作确定了具有从头错义和无义GRIA 1变体的受试者。对受试者进行了详细的表型和遗传评估，并在体外评估了变体的致病性，以表征AMPAR功能和表达的变化。此外，建立了两个非洲爪蟾1 CRISPR-Cas9 F0模型以表征体内结果。发现了7个具有罕见GRIA 1变异的无关个体。1个个体携带纯合无义变异（p.Arg377Ter），6个个体携带杂合错义变异（p.Arg345Gln、p.Ala636Thr、p.Ile627Thr和p.Gly745Asp），其中3个个体反复出现p.Ala636Thr变异。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GRIA 1变体突变的主要含GluA 1的AMPAR亚型的功能评估表明，四种错义变体中有三种严重干扰受体功能。纯合停止增益变体完全破坏了含GluA 1的AMPAR的表达。非洲爪蟾gria 1模型表现出短暂的运动缺陷，间歇性癫痫发作表型，并显着损害突变体的工作记忆。这些数据支持由GRIA 1中影响AMPAR功能的杂合和纯合变体引起的发育障碍。
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.
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影响因子：
5.4
作者：
Cleal M;Fontana BD;Ranson DC;McBride SD;Swinny JD;Redhead ES;Parker MO
通讯作者：
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影响因子：
25
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Geisheker MR;Heymann G;Wang T;Coe BP;Turner TN;Stessman HAF;Hoekzema K;Kvarnung M;Shaw M;Friend K;Liebelt J;Barnett C;Thompson EM;Haan E;Guo H;Anderlid BM;Nordgren A;Lindstrand A;Vandeweyer G;Alberti A;Avola E;Vinci M;Giusto S;Pramparo T;Pierce K;Nalabolu S;Michaelson JJ;Sedlacek Z;Santen GWE;Peeters H;Hakonarson H;Courchesne E;Romano C;Kooy RF;Bernier RA;Nordenskjöld M;Gecz J;Xia K;Zweifel LS;Eichler EE
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影响因子：
64.5
作者：
Dürr KL;Chen L;Stein RA;De Zorzi R;Folea IM;Walz T;Mchaourab HS;Gouaux E
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作者：
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通讯作者：
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作者：
Chourbaji, S.;Vogt, M. A.;Gass, P.
通讯作者：
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