GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.
GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.
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DOI：
10.1038/jhg.2017.19
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发表时间：
2017-06
影响因子：
3.5
通讯作者：
Pierson TM
中科院分区：
文献类型：
--
作者：
Chen W;Shieh C;Swanger SA;Tankovic A;Au M;McGuire M;Tagliati M;Graham JM;Madan-Khetarpal S;Traynelis SF;Yuan H;Pierson TM
n -甲基- d -天冬氨酸受体（NMDARs）在大脑发育和神经系统疾病中发挥重要作用。我们报告了两个具有相似的显性新生GRIN1突变的个体（c.1858）1858年G > C;p.G620R)。这两个个体在出生时都表现出发育迟缓和低张力，并伴有行为异常和刻板动作。我们评估了含有突变体GluN1-G620R和GluN2A或GluN2B的重组NMDARs向质膜运输的变化及其电生理特性。GluN1-G620R/GluN2A复合物显示运输轻度减少，谷氨酸和甘氨酸的效力降低约2倍，对Mg2+阻滞的敏感性强烈降低，并且对最大有效浓度的激动剂的当前反应显着降低。GluN1-G620R/GluN2B复合物显示出与类似的电生理改变相关的细胞表面蛋白质递送显著减少。这些结果表明，这些个体可能由于在胚胎脑发育期间神经元表面GluN1-G620R/GluN2B复合物的存在减少以及出生后含有GluN1-G620R的NMDARs的电流反应减少而遭受神经发育缺陷。这些病例强调了对新生突变进行全面功能表征的重要性，并说明了NMDAR表达、运输和功能的几个不同特征的组合如何存在并影响表型。
N-methyl-D-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G>A and c.1858 G>C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties. GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~ 2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg2+ block, and a significant reduction of current responses to a maximal effective concentration of agonists. GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface associated with similarly altered electrophysiology. These results indicate these individuals may have suffered neurodevelopmental deficits as a result of the decreased presence of GluN1-G620R/GluN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of GluN1-G620R-containing NMDARs after birth. These cases emphasize the importance of comprehensive functional characterization of de novo mutations and illustrates how a combination of several distinct features of NMDAR expression, trafficking and function can be present and influence phenotype.
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影响因子：
30.8
作者：
Carvill, Gemma L.;Regan, Brigid M.;Yendle, Simone C.;O'Roak, Brian J.;Lozovaya, Natalia;Bruneau, Nadine;Burnashev, Nail;Khan, Adiba;Cook, Joseph;Geraghty, Eileen;Sadleir, Lynette G.;Turner, Samantha J.;Tsai, Meng-Han;Webster, Richard;Ouvrier, Robert;Damiano, John A.;Berkovic, Samuel F.;Shendure, Jay;Hildebrand, Michael S.;Szepetowski, Pierre;Scheffer, Ingrid E.;Mefford, Heather C.
通讯作者：
Mefford, Heather C.
DOI：
10.1073/pnas.93.24.14170
发表时间：
1996-11-26
影响因子：
11.1
作者：
Sharma, G;Stevens, CF
通讯作者：
Stevens, CF
影响因子：
4
作者：
Burnashev, Nail;Szepetowski, Pierre
通讯作者：
Szepetowski, Pierre
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
9.9
作者：
Lemke JR;Geider K;Helbig KL;Heyne HO;Schütz H;Hentschel J;Courage C;Depienne C;Nava C;Heron D;Møller RS;Hjalgrim H;Lal D;Neubauer BA;Nürnberg P;Thiele H;Kurlemann G;Arnold GL;Bhambhani V;Bartholdi D;Pedurupillay CR;Misceo D;Frengen E;Strømme P;Dlugos DJ;Doherty ES;Bijlsma EK;Ruivenkamp CA;Hoffer MJ;Goldstein A;Rajan DS;Narayanan V;Ramsey K;Belnap N;Schrauwen I;Richholt R;Koeleman BP;Sá J;Mendonça C;de Kovel CG;Weckhuysen S;Hardies K;De Jonghe P;De Meirleir L;Milh M;Badens C;Lebrun M;Busa T;Francannet C;Piton A;Riesch E;Biskup S;Vogt H;Dorn T;Helbig I;Michaud JL;Laube B;Syrbe S
通讯作者：
Syrbe S