In this issue of Brain David Brenner and colleagues report a hot-spot of mutations in the kinesin family gene KIF5A causing familial amyotrophic lateral sclerosis, adding to the existing genetic evidence implicating altered cytoskeletal function and intracellular transport in this disease. Two other papers broaden the range of manifestations of genetic disorders involving glutamate receptors. Juliette Piard, George Umanah, Frederike Harms and co-workers identify a mutation in the AAA+ family ATPase Thorase, encoded by ATAD1, which leads to lethal encephalopathy and arthrogryposis, while Andrew Fry, Katherine Fawcett and colleagues report an association between de novo mutations of GRIN1, which codes for the GluN1 subunit of NMDA receptors, and extensive bilateral polymicrogyria, with several probands presenting with developmental delay, microcephaly, visual impairment or refractory epilepsy. The association between NMDA receptors and abnormalities of cortical development is especially intriguing, because previous reports on GRIN1 mutations have only identified relatively minor structural abnormalities in association with various levels of intellectual disability, epilepsy or movement disorders. Some of the polymicrogyria-associated mutations were shown to confer a gain of function, providing a tentative link to animal studies that have used NMDA receptor agonists to induce cortical malformations.

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社论

在本期《大脑》中， David Brenner及其同事报道了驱动蛋白家族基因KIF5A突变的热点，该突变导致家族性肌萎缩性侧索硬化症，并增加了现有遗传证据，表明该疾病的细胞骨架功能和细胞内运输发生了改变。另外两篇论文拓宽了涉及谷氨酸受体的遗传疾病的表现范围。朱丽叶皮亚尔，乔治Umanah，Frederike危害和同事确定在AAA +家庭ATP酶Thorase的突变，通过编码ATAD1，从而导致致命性脑病及关节挛缩，而安德鲁·弗莱，凯瑟琳·福西特和同事报告之间的关联从头突变GRIN1，它编码NMDA受体的GluN1亚基，以及广泛的双侧多小胶质细胞增多症，一些先证者出现发育迟缓，小头畸形，视力障碍或难治性癫痫。NMDA受体与皮质发育异常之间的关联尤其令人着迷，因为先前有关GRIN1突变的报道仅发现了与各种水平的智力障碍，癫痫或运动障碍相关的相对较小的结构异常。已显示一些与多微gyria相关的突变赋予功能增强，为使用NMDA受体激动剂诱导皮层畸形的动物研究提供了初步联系。