Zoghbi H Y
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Clin Neurosci. 1995;3(1):5-11.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant progressive neurodegenerative disorder characterized by ataxia, dysarthria, ophthalmoparesis, and variable degrees of amyotrophy and neuropathy. Symptoms usually develop in the third or fourth decade but anticipation has been noted in juvenile onset cases. Neuropathologic findings include severe neuronal loss in the cerebellum and brainstem as well as degeneration of spinocerebellar tracts. The SCA1 gene which maps to the short arm of human chromosome 6 was identified using a positional cloning approach. The disease causing mutation is an expansion of a CAG trinucleotide repeat which lies within the coding region of a novel protein, ataxin-1, and encodes a polyglutamine tract. The number of CAG repeats varies from 6-39 repeats on normal alleles and 40-81 repeats on SCA1 alleles. The repeat has a perfect CAG configuration on expanded alleles whereas it is interrupted by 1-3 CAT units on normal alleles. Both wild type and expanded alleles are transcribed, ruling out impairment of transcriptional efficiency in SCA1. A pathogenetic model is proposed based on the findings in SCA1 and other neurodegenerative diseases caused by expansion of polyglutamine tracts. The expanded polyglutamine tract in ataxin-1 may lead to neurodegeneration through a gain of function mechanism involving aberrant interactions with other molecules in the involved neurons.
1型脊髓小脑共济失调（SCA1）是一种常染色体显性进行性神经退行性疾病，其特征为共济失调、构音障碍、眼球运动障碍以及不同程度的肌萎缩和神经病变。症状通常在第三或第四个十年出现，但在青少年发病的病例中已观察到遗传早现现象。神经病理学发现包括小脑和脑干中严重的神经元丧失以及脊髓小脑束的变性。利用定位克隆方法鉴定出了定位于人类6号染色体短臂的SCA1基因。致病突变是一个CAG三核苷酸重复序列的扩增，该重复序列位于一种新蛋白ataxin-1的编码区域内，并编码一个多聚谷氨酰胺序列。正常等位基因上CAG重复序列的数量为6 - 39次重复，而SCA1等位基因上为40 - 81次重复。在扩增的等位基因上，该重复序列具有完美的CAG结构，而在正常等位基因上则被1 - 3个CAT单位中断。野生型和扩增的等位基因均被转录，排除了SCA1中转录效率受损的情况。基于SCA1以及其他由多聚谷氨酰胺序列扩增引起的神经退行性疾病的研究结果，提出了一种发病机制模型。ataxin-1中扩增的多聚谷氨酰胺序列可能通过一种功能获得机制导致神经退行性变，该机制涉及与受累神经元中其他分子的异常相互作用。
