De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.
De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.
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DOI：
10.1093/brain/awx358
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发表时间：
2018-03-01
期刊：
影响因子：
--
通讯作者：
Pilz DT
中科院分区：
文献类型：
--
作者：
Fry AE;Fawcett KA;Zelnik N;Yuan H;Thompson BAN;Shemer-Meiri L;Cushion TD;Mugalaasi H;Sims D;Stoodley N;Chung SK;Rees MI;Patel CV;Brueton LA;Layet V;Giuliano F;Kerr MP;Banne E;Meiner V;Lerman-Sagie T;Helbig KL;Kofman LH;Knight KM;Chen W;Kannan V;Hu C;Kusumoto H;Zhang J;Swanger SA;Shaulsky GH;Mirzaa GM;Muir AM;Mefford HC;Dobyns WB;Mackenzie AB;Mullins JGL;Lemke JR;Bahi-Buisson N;Traynelis SF;Iago HF;Pilz DT
NMDA受体激动剂已多年来用于产生多毛糖的动物模型，这是皮质发育的畸形。 Fry等。确定11例患有严重双侧多糖类患者的Novo Grin1突变。在特定蛋白质结构域中与多糖蛋白相关的GRIN1突变簇，并显着改变NMDA受体功能。
多糖瘤是皮质发育的畸形。多毛毛病的病因仍然知之甚少。使用全外观测序，我们在57个带有多粒细胞的57个父源三下三重点中的2个中发现了从头杂合的错义grin1突变。我们发现其他皮质畸形患者中有9个从头失误的Grin1突变。患者的共同特征是与严重发育延迟，产后小头畸形，皮质视觉障碍和顽固性癫痫有关的广泛的双侧多糖瘤。 GRIN1编码Glun1，这是N-甲基-D-天冬氨酸受体的基本亚基。与多毛素相关的GRIN1突变趋向于聚集在S2区域（Glun1的配体结合结构域的一部分）或相邻的M3螺旋。这些区域很少在正常人群中或无多聚糖的GRIN1患者中突变。使用两电极和全细胞电压钳分析，我们表明多肌糖相关的Grin1突变显着改变了受体的体外活性。其中三个突变增加了激动剂的效力，而一个突变减少了受体的质子抑制作用。这些结果令人惊讶，因为以前的GRIN1突变通常导致功能的丧失，并且由于已使用了多年来使用N-甲基-D-天冬氨酸受体激动剂来产生多毛糖的动物模型。总体而言，我们的结果扩大了与Grin1突变相关的表型光谱，并突出了N-甲基-D-天冬氨酸受体信号传导在多毛糖的发病机理中的重要作用。
NMDA receptor agonists have been used for many years to generate animal models of polymicrogyria, a malformation of cortical development. Fry et al. identify de novo GRIN1 mutations in eleven patients with severe bilateral polymicrogyria. Polymicrogyria-associated GRIN1 mutations cluster in specific protein domains and significantly alter NMDA receptor function. Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.
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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.
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
3.4
作者：
Law, AJ;Weickert, CS;Harrison, PJ
通讯作者：
Harrison, PJ
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
64.8
作者：
Iwasato, T;Datwani, A;Itohara, S
通讯作者：
Itohara, S