SCA42の臨床と分子病態機序

抄録

Spinocerebellar degeneration (SCD) is a genetically heterogeneous disorder. To date, 41 genetic loci with autosomal dominant inheritance have been reported, and 30 causative genes have been elucidated. In order to identify a new causative gene, we analyzed a large family with dominant inherited SCD. We performed linkage analysis based on high–density SNP typing and exome sequencing. We used the whole cell patch–clamp technique to assess the electrophysiological change caused by mutation. In addition, differentiation into cerebellar Purkinje cells was conducted using iPS cells derived from the patients.

From the result of genetic analysis, we identified CACNA1G encoding Ca_V3.1 one of voltage–dependent calcium channels as a new causative gene, the phenotype termed SCA42. The same mutation was also observed in another SCD family. The patients exhibited pure cerebellar ataxia and some of them showed remarkable tremor. Ages at onset were varied from 18 to 70 years old. Ca_V3.1 is classified as low–voltage–activated (T–type) calcium channel and abundantly expressed in central nervous system including the cerebellum. The mutation we identified was located in the fourth segment (S4) of repeat IV. S4 of each repeat is a very important domain as a voltage sensor. From the result of electrophysiological study, the current change due to the prepulse was shifted toward positive membrane potential in the mutant compared with the wild–type. No morphological and immunocytochemical changes were observed in differentiation into Purkinje cells.

Many subtypes of SCD are caused by abnormal extension of repetitive sequences. In recent years, mutations in several channel–coding genes including calcium channels have been reported as the causes of SCDs. It is expected that investigation of SCD pathology as a channel disorder will contribute to further comprehension of the disease mechanism.