Genes for endosomal NHE6 and NHE9 are misregulated in autism brains.
Genes for endosomal NHE6 and NHE9 are misregulated in autism brains.
复制标题
自闭症大脑中内体 NHE6 和 NHE9 的基因被错误调节。
DOI：
10.1038/mp.2013.28
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发表时间：
2014
影响因子：
11
通讯作者：
Morrow,EM
中科院分区：
文献类型：
--
作者：
Schwede,M;Garbett,K;Mirnics,K;Geschwind,DH;Morrow,EM
自闭症是一种高度异质性的神经发育障碍，语言、社交沟通受损，兴趣和行为受限且重复。具有自闭症特征的单基因发育性脑疾病，如Rett综合征、Angelman综合征、脆性X综合征等，提供了与严重自闭症相关的重要易处理模型。除了在单基因条件下观察自闭症症状外，如果负责的基因在特发性自闭症患者的大脑中也显著失调，那么这些数据为该基因在自闭症病理生理学中的重要性提供了实质性的独立支持。鉴于这一逻辑，我们开始测试特发性自闭症患者死后脑组织中编码钠/氢交换蛋白家族的感兴趣基因是否存在基因表达变化，特别是对定位于内体的交换器的形式，即NHE6和NHE9。X连锁内体钠/氢交换器6(NHE6，也称为SLC9A6)的突变代表了一种新的神经遗传学综合征，具有不同的表达能力。1在对200个X连锁智力障碍家系的X染色体编码外显子进行系统、大规模的重新测序筛选中，NHE6是最常发生突变的六个基因之一。2根据最初的临床描述，“克里斯汀森综合症”报告了与自闭症症状有关的问题，后来也有报道。3，4与NHE6突变相关的自闭症症状的描述平行，Morrow等人。5发表了高度相关的内体蛋白NHE9在严重自闭症合并癫痫中的突变。内体过程，如NHE6和NHE9的突变所提示的，代表了关于认知发育障碍研究的重要细胞机制。有趣的是，在前六名中
Autism is a highly heterogeneous neurodevelopmental disorder with impaired language, social communication, and restricted and repetitive interests and behavior. Monogenic developmental brain disorders with autism features such as Rett syndrome, Angelman syndrome, Fragile X syndrome, and others provide important tractable models of relevance to severe autism. In addition to observing autism symptoms in the monogenic condition, if the gene responsible is also significantly misregulated in the brains of people with idiopathic autism, then these data provide substantial independent support for the importance of the gene in autism pathophysiology.Given this logic, we set out to test if there were gene expression changes in postmortem brain tissue from patients with idiopathic autism in the genes of interest that encode the Naþ/Hþ exchanger family of proteins, with particular interest in the forms of exchangers localized to endosomes, namely, NHE6 and NHE9. Mutations in the X-linked endosomal Naþ/Hþ Exchanger 6 (NHE6, also known as SLC9A6) represent a novel neurogenetic syndrome with variable expressivity. 1 In a systematic, large-scale resequencing screen of X-chromosome coding exons in> 200 pedigrees consistent with X-linked intellectual disability, NHE6 was among the top six most recurrently mutated genes. 2 The ‘Christianson syndrome’, based on the initial clinical description, reported an association with autistic symptoms as has been reported subsequently. 3, 4 In parallel to the description of autistic symptoms associated with mutations in NHE6, Morrow et al. 5 published mutations in the highly related endosomal protein NHE9 in severe autism with epilepsy. Endosomal processes, such as would be suggested by mutations in NHE6 and NHE9, represent an important cellular mechanism for investigations regarding disorders of cognitive development. Interestingly, of the six top