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.

中文翻译：

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GRIN1 的从头突变导致广泛的双侧多小脑回


多小脑回是皮质发育的畸形。多小脑回的病因学仍知之甚少。通过全外显子组测序，我们在 57 个患有多小脑回的亲子三人组中的 2 个中发现了新生杂合错义GRIN1突变。我们在其他皮质畸形患者中发现了 9 个新的GRIN1错义突变。这些患者的共同特征是广泛的双侧多小脑回，伴有严重发育迟缓、出生后小头畸形、皮质视觉障碍和顽固性癫痫。 GRIN1编码 GluN1， N-甲基-d-天冬氨酸受体的重要亚基。多小脑回相关的GRIN1突变倾向于聚集在 S2 区域（GluN1 配体结合域的一部分）或邻近的 M3 螺旋。这些区域在正常人群或没有多小脑回的GRIN1患者中很少发生突变。使用两电极和全细胞电压钳分析，我们发现与多小脑回相关的GRIN1突变显着改变受体的体外活性。其中三种突变增加了激动剂效力，而一种突变降低了受体的质子抑制。这些结果是惊人的，因为以前的GRIN1突变通常会导致功能丧失，而且N-甲基-d-天冬氨酸受体激动剂多年来一直用于生成多小脑回动物模型。 总体而言，我们的结果扩大了与GRIN1突变相关的表型谱，并强调了N-甲基-d-天冬氨酸受体信号传导在多小脑回发病机制中的重要作用。