Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.
Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.
复制标题
DOI：
10.1212/wnl.0000000000002740
复制
发表时间：
2016-06-07
期刊：
影响因子：
9.9
通讯作者：
Syrbe S
中科院分区：
文献类型：
--
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
确定编码NMDA受体亚基GluN1的GRIN1突变引起的表型谱，并研究其潜在的功能病理生理学。我们收集了来自多个诊断和研究队列的分子和临床数据。GRIN 1突变的功能后果进行了研究非洲爪蟾卵母细胞。我们在14例患者中发现了GRIN1的杂合子从头突变，并回顾了所有9例先前报道的患者的表型。这23个人提出了一个独特的表型的深度发育迟缓，严重的智力残疾，缺乏语言，肌肉张力减退，多动性运动障碍，动眼危象，皮质盲，全身性脑萎缩，癫痫。突变聚集在跨膜区段内，并导致不同严重程度的通道功能丧失，具有显性负效应。此外，我们描述了2个纯合子GRIN 1突变（1个错义，1个截断），每个分离与严重的神经发育表型在血缘家庭。从头GRIN1突变与严重的智力残疾相关，皮质视觉障碍以及眼功能障碍和运动障碍是区别性的表型特征。NMDA受体功能的丧失似乎是潜在的疾病机制。杂合和纯合突变的鉴定模糊了GRIN 1相关疾病的显性和隐性遗传的界限。
To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.