MJD1基因单个碱基多态性与CAG重复序列不稳定性的关系

Single base polymorphism in MJD1 gene associated with the instability of CAG repeat

马查多－约瑟夫病患者的ＭＪＤ１基因存在ＣＡＧ三核苷酸不稳定扩展突变，为探讨这种不稳定扩展突变的分子机制。方法对５８名正常人和２０名ＭＪＤ患者的ＭＪＤ１基因内ＣＡＧ／ＣＡＡ、ＣＧＧ／ＧＧＧ两个位点的多态性进行检测。结果正常染色体中，具有ＣＧＧ等位基因的ＣＡＧ重复数目（２７．３２±０．６１，ｎ＝２８）较具有ＧＧＧ等位基因的ＣＡＧ重复数目（１５．９０±０．６９，ｎ＝３０）明显大（Ｐ＜０．０１）。ＣＧＧ等位基因在患者中的分布频率（１００％）明显高于正常人（４８．３％）。结论ＭＪＤ１基因内单个碱基置换影响ＣＡＧ重复序列的稳定性。

Objective Machado Joseph disease(MJD) is an autosomal dominant inherited spinocerebellar degeneration charcterized by cerebellar ataxia and pyramidal signs with dystonia and amyotrophy as the major neurologic signs. The causative mutation has recently been discovered as the expansions of unstable CAG trinucleotide repeat in the MJD1 gene on chromosome 14q32.1. Recent investigations have suggested the involvement of predisposing chromosomes or cis acting factors in the instability of trinucleotide repeat in the disease caused by trinucleotide repeat expansions. We considered that polymorphic single base substitutions flanking the CAG repeat(one being CAG/CAA polymorphism located within the CAG repeat, and the other being CGG/GGG polymorphism located near the 3' end of CAG repeat) was quite suitable to test the hypothesis. Method We analyzed the two intragenic polymorphisms in the MJD1 genes of 58 normal chromosomes and 20 affected chromosomes in the patients with Machado Joseph disease in the Chinese MJD families. Results The results indicated that the CAG allele was associated with the larger CAG repeat lengths on normal chromosomes (27.32±0.61, n=28) compared with those of the GGG allele (15.9±0.69,n=30). In addition, the CGG allele was much more frequent in the MJD affected chromosomes (100%) than in the normal chromosomes (48.3%). In the former an apparent disequilibrium was found. Conclusion These finding supported the hypothesis that the single base substitution at the 3' end of CAG repeat affected the instability of the CAG trinucleotide repeat.