Ataxia-ocular apraxia 2

Ataxia-ocular apraxia 2

筆者らはataxia-ocular apraxia 2（AOA2）（MIM 608465）の日本人3家系を経験した。AOA2は臨床的には，常染色体劣性の遺伝形式，若年発症，小脳萎縮，末梢神経障害，血清α-フェトプロテイン高値，良好な生命予後，ocular apraxiaなどを特徴とする脊髄小脳変性症である。その原因遺伝子は9番染色体長腕上（9q34）に存在する。その責任遺伝子（SETX）がコードする蛋白は，酵母のSen1pと高い相同性を有することよりsenataxinと命名された。Senataxinは2,677アミノ酸からなる巨大な蛋白であり，C末側にヘリカーゼドメインを有する。Senataxinのある種の遺伝子変異はamyotrophic lateral sclerosis 4（ALS4）を起こす。Sen1pの機能からsenataxinは，DNAヘリカーゼやRNAヘリカーゼの活性を持つ以外に，種々のRNAクラスの代謝に関与している可能性が考えられる。Senataxinの遺伝子変異が神経細胞死を来す機序について，今後の解明が期待される。

Ataxia-ocular apraxia 2（AOA2）is a slowly progressive cerebellar ataxia characterized by autosomal recessive inheritance, juvenile onset, cerebellar atrophy, sensory-motor neuropathy, high serum alpha-fetoprotein（AFP）levels, and oculomotor apraxia. However, although almost all patients have elevated AFP levels, oculomotor apraxia is only observed in 47％ of cases. Thus the disease name AOA2 could be misleading in some cases. The responsible gene（SETX）maps to chromosome 9q34 and comprises an open reading frame of 8,031 nucleotides and 24 exons. Northern blot and reverse transcription polymerase chain reaction analyses revealed that it is ubiquitously expressed in all examined organs, including the brain. Senataxin, the protein encoded by SETX, has extensive homologies with the fungal Sen1 proteins, a family of tRNA splicing endonuclease proteins. Senataxin consists of 2,677 amino acids with a helicase domain at the C terminus, placing it in the superfamily 1 of helicases. We have analysed three Japanese families with AOA2. Gene analysis showed that Family 1 is homozygous for the nonsense mutation c.4321C→T, resulting in truncation at amino acid residue 1440, whereas Family 2 is homozygous for the missense mutation c.6638C→T（p.P2213L）. The disease causing mutation for Family 3 has not yet been identified. The functions of Sen1p, the fungal ortholog of senataxin, suggest that senataxin has both DNA and RNA helicase activity and is involved in the metabolism of diverse RNA classes. Interestingly, amyotrophic lateral sclerosis 4, a juvenile-onset and slowly progressive motor neuron disease with an autosomal dominant trait of inheritance, was found to be allelic to AOA2. Family 2 and 3 have long disease duration with severe atrophy and unique deformity of their hands, suggesting an impairment of motor neurons in AOA2. Therefore, there may be some overlap of clinical manifestations between these two disorders. Further study will be required to elucidate the mechanisms whereby mutations of senataxin cause neuronal death.