Ishikawa Kinya, Ishiguro Taro, Takahashi Makoto, Sato Nozomu, Amino Takeshi, Niimi Yusuke, Mizusawa Hidehiro
Department of Neurology and Neurological Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Rinsho Shinkeigaku. 2009 Nov;49(11):907-9. doi: 10.5692/clinicalneurol.49.907.
Spinocerebellar ataxia (SCA) is a group of degenerative ataxias with autosomal dominant inheritance. The most common form of mutation that causes SCA is the expansion of trinucleotide (CAG) repeat encoding polyglutamine. These "polyglutamine disorders" are, SCA1, SCA2, Machado-Joseph disease, SCA6, SCA7, SCA17 and DRPLA. Another dynamic mutation, yet a non-coding one, has been identified as the cause of SCA8, SCA10 and SCA12. This mutation includes, trinucleotide (CAG/CTG) expansion causing SCA8 and SCA12, and pentanuclotide (ATTCT) expansion leading SCA10. In addition to these dynamic mutations, static mutations, such as missense mutations and deletions, have been identified to cause SCA5, SCA11, SCA13, SCA14, SCA15 and SCA27. Since 1992, authors have been involved in identifying the mutation (s) of autosomal dominant cerebellar ataxia with rather pure cerebellar syndrome (ADCAIII). About a half of our cohort with ADCAIII were SCA6, caused by a small CAG repeat expansion in the alpha1A-voltage-dependent calcium channel gene. Recent study in patients' brains suggested that a small polyglutamine expansion leads a portion of this channel protein to aggregate in the Purkinje cell. Another type of ADCAIII is the chromosome 16q22.1-linked ADCA. By a comprehensive positional cloning strategy, we have found a genetic change that segregate with the disease. Identifying the mutation of 16q-ADCA is imperative for understanding molecular basis of this disease.
脊髓小脑共济失调(SCA)是一组常染色体显性遗传的退行性共济失调疾病。导致SCA最常见的突变形式是编码多聚谷氨酰胺的三核苷酸(CAG)重复序列的扩增。这些“多聚谷氨酰胺疾病”包括SCA1、SCA2、马查多-约瑟夫病、SCA6、SCA7、SCA17和齿状核红核苍白球路易体萎缩症(DRPLA)。另一种动态突变,尽管是非编码突变,已被确定为SCA8、SCA10和SCA12的病因。这种突变包括导致SCA8和SCA12的三核苷酸(CAG/CTG)扩增,以及导致SCA10的五核苷酸(ATTCT)扩增。除了这些动态突变外,还发现了一些静态突变,如错义突变和缺失,可导致SCA5、SCA11、SCA13、SCA14、SCA15和SCA27。自1992年以来,作者一直致力于鉴定具有相当纯小脑综合征的常染色体显性遗传性小脑共济失调(ADCAIII)的突变。我们研究的约一半ADCAIII患者为SCA6,由α1A-电压依赖性钙通道基因中的小CAG重复扩增引起。最近对患者大脑的研究表明,小的多聚谷氨酰胺扩增会导致该通道蛋白的一部分在浦肯野细胞中聚集。另一种类型的ADCAIII是与16q22.1染色体连锁的ADCA。通过全面的定位克隆策略,我们发现了一种与疾病相关的基因变化。鉴定16q-ADCA的突变对于理解该疾病的分子基础至关重要。