臨床神経学

第48回日本神経学会総会

<教育講演8>
遺伝性脊髄小脳変性症の臨床と分子遺伝学

佐々木 秀直

北海道大学大学院医学研究科 神経内科学分野〔〒060-8638 札幌市北区北15条西7丁目〕

Hereditary spinocerebellar ataxia (SCA) is a cluster of heterogeneous disorders. At now, 29 dominant loci have been assigned. Responsible genes and mutations are determined in at least 14 of them. In recessive and X-linked SCAs, 15 loci have been mapped, and mutation in each gene is determined by 6 disorders. Molecular mechanism of those SCAs are variable. Generally, deletion, insertion, or substitution in a gene modifies the primary structure of mRNA, subsequently resulting in disturbance of transcription or in translation of mutant proteins showing loss-of-function or dominant negative effect. Large expansion of tandem repeat in promotor region or intron suppress translation of the gene, thus causing similar effect. Expansion of (CAG)n in coding exon is translated into proteins containing elongated poly-Q. Since the poly-Q fragment is cytotoxic, this kind of mutation causes protein toxic gain-of-function. In addition, RNA toxic gain-of-function mechanism recently gains attention as a new molecular mechanism of SCA8 and SCA10.
Clinically, dominant SCA with dynamic mutation shows variable onset of age, severity, and variation of clinical phenotypes. Among this clinical complexity, vocal cord abductor paralysis in SCA1, familial parkinsonism in SCA2, vestibular dysfunction and axonal neuropathy in MJD, and axial myoclonus in SCA14, are reviewed for potential usefulness in clinical practice.

(臨床神経, 47:795−800, 2007)
key words:脊髄小脳変性症, 動的変異, 機能喪失変異, 機能獲得変異, RNAスプライシング

(受付日:2007年5月16日)