Department of Neurology, The University of Chicago, Chicago, 60637, IL, USA.
Adv Exp Med Biol. 2018;1049:147-173. doi: 10.1007/978-3-319-71779-1_7.
Spinocerebellar ataxia (SCA) type 6 is an autosomal dominant disease affecting cerebellar degeneration. Clinically, it is characterized by pure cerebellar dysfunction, slowly progressive unsteadiness of gait and stance, slurred speech, and abnormal eye movements with late onset. Pathological findings of SCA6 include a diffuse loss of Purkinje cells, predominantly in the cerebellar vermis. Genetically, SCA6 is caused by expansion of a trinucleotide CAG repeat in the last exon of longest isoform CACNA1A gene on chromosome 19p13.1-p13.2. Normal alleles have 4-18 repeats, while alleles causing disease contain 19-33 repeats. Due to presence of a novel internal ribosomal entry site (IRES) with the mRNA, CACNA1A encodes two structurally unrelated proteins with distinct functions within an overlapping open reading frame (ORF) of the same mRNA: (1) α1A subunit of P/Q-type voltage gated calcium channel; (2) α1ACT, a newly recognized transcription factor, with polyglutamine repeat at C-terminal end. Understanding the function of α1ACT in physiological and pathological conditions may elucidate the pathogenesis of SCA6. More importantly, the IRES, as the translational control element of α1ACT, provides a potential therapeutic target for the treatment of SCA6.
脊髓小脑性共济失调 6 型（SCA6）是一种常染色体显性遗传疾病，影响小脑退行性变。临床上，其特征为单纯小脑功能障碍，步态和站立不稳进行性缓慢加重，构音障碍，眼球运动异常，发病较晚。SCA6 的病理学发现包括浦肯野细胞弥漫性丧失，主要位于小脑蚓部。遗传上，SCA6 是由 19p13.1-p13.2 染色体上最长同工型 CACNA1A 基因最后外显子中三核苷酸 CAG 重复扩展引起的。正常等位基因有 4-18 个重复，而致病等位基因含有 19-33 个重复。由于存在具有 mRNA 的新型内部核糖体进入位点（IRES），CACNA1A 在同一 mRNA 的重叠开放阅读框（ORF）内编码两个结构上不相关的具有不同功能的蛋白质：（1）P/Q 型电压门控钙通道的α1A 亚基；（2）α1ACT，一种新发现的转录因子，其 C 末端具有多聚谷氨酰胺重复。了解α1ACT 在生理和病理条件下的功能可能阐明 SCA6 的发病机制。更重要的是，IRES 作为 α1ACT 的翻译控制元件，为治疗 SCA6 提供了一个潜在的治疗靶点。
