Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1
Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1
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DOI：
10.1016/j.ajhg.2012.07.019
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发表时间：
2012-09-07
影响因子：
9.8
通讯作者：
Kalaydjieva, Luba
中科院分区：
文献类型：
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作者：
Guergueltcheva, Velina;Azmanov, Dimitar N.;Kalaydjieva, Luba
在罗姆人患者中发现了常染色体隐性先天性小脑共济失调，其起源于具有已知强创始人效应的小亚分离株。患者表现为整体发育迟缓、中度至重度站立和步态共济失调、构音障碍、轻度轮换运动障碍、辨认困难和震颤、智力缺陷和轻度锥体征。脑成像显示一些患者出现进行性全身性小脑萎缩，下蚓部发育不全和/或大脑结构较小。外显子组测序用于对提取的 SNP 基因型进行连锁分析和突变检测，鉴定出两个新的（即在任何数据库中未发现）变异，它们位于独特的 6q24 连锁区域内，相距 7 bp。这两种突变在五个受影响的家庭中与疾病共分离，其中所有十名患者都是纯合子。突变基因GRM1编码代谢型谷氨酸受体mGluR1，该受体在小脑浦肯野细胞中高表达，在小脑发育和突触可塑性中发挥重要作用。这两种突变影响对选择性剪接和受体亚型生成至关重要的基因区域；它们是 3 bp 外显子 8 缺失和内含子 8 剪接突变（分别为 c.2652_2654del 和 c.2660+2T>G [RefSeq 登录号 NM_000838.3]）。缺失的功能影响尚不清楚，并且被剪接缺陷所掩盖。尽管共济失调类淋巴母细胞系表达 GRM1 的水平与对照细胞相当，但异常转录物跳过了外显子 8 或终止于内含子 8，并编码各种类型的非功能性受体，这些受体要么缺乏跨膜结构域，要么含有异常的细胞内尾部，要么完全缺失尾部。该研究表明 mGluR1 与人类遗传性共济失调有关。它还说明了罗姆人创始人群体通过外显子组测序进行突变识别的潜力。
Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1 encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail. The study implicates mGluR1 in human hereditary ataxia. It also illustrates the potential of the Roma founder populations for mutation identification by exome sequencing.