Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease.
Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease.
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MJD1 基因 CAG 重复代际不稳定性的证据，以及患有马查多-约瑟夫病的日本和白种人受试者中侧翼标记保守单倍型的证据。
DOI：
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发表时间：
1995
影响因子：
3.5
通讯作者：
P. S. George
中科院分区：
文献类型：
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作者：
Y. Takiyama;S. Igasrashi;E. Rogaeva;K. Endo;E. Rogaev;Hirosato Tanaka;R. Sherrington;K. Sanpei;Yan Liang;M. Saito;T. Tsuda;H. Takano;M. Ikeda;Chih;H. Chi;J. Kennedy;A. Lang;J. Wherrett;M. Segawa;Y. Nomura;T. Yuasa;J. Weissenbach;M. Yoshida;M. Nishizawa;K. Kidd;S. Tsuji;P. S. George
在一大群患有马查多-约瑟夫病 (MJD) 的日本和白人受试者中，检查了 MJD1 基因 3' 端的 (CAG)n 重复序列的大小以及 MJD1 基因周围一系列微卫星标记的单倍型。我们的数据提供了五项新颖的观察结果。首先，在大多数日本人和白种人受试者中，MJD 与阵列从 14-37 个重复的正常范围扩大到 68-84 个重复有关，但没有观察到受试者的扩张程度介于正常组和 MJD 受影响组之间。其次，与 MJD 相关的扩展等位基因表现出代际不稳定性，特别是在雄性减数分裂中，并且这种不稳定性与预期的临床现象相关。第三，扩展等位基因的大小不仅与 MJD 的发病年龄呈负相关（r = -0.738，p < 0.001），而且还与其他临床特征的频率相关 [例如，假性突眼和锥体征在重复次数较多的受试者中更为常见（分别为 p < 0.001 和 p < 0.05）]。第四，在扩展等位基因纯合子的受试者中，疾病表型明显更严重并且发病年龄较早（16岁），这与亨廷顿病形成对比，表明MJD1基因中的扩展等位基因可以通过显性负效应（假定在HD中排除）或通过针对HD提出的功能获得效应来发挥其作用。最后，患有 MJD 的日本人和白种人受试者在 MJD1 基因周围的几个标记处具有相同的单倍型，这在正常的日本人和白种人人群中并不常见，这表明这些人群中存在共同的创始人，或者存在易受 MJD1 基因中 CAG 重复病理性扩张影响的染色体。
The size of the (CAG)n repeat array in the 3' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD). Our data provide five novel observations. First, MJD is associated with expansion fo the array from the normal range of 14-37 repeats to 68-84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups. Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meioses, and this instability was associated with the clinical phenomenon of anticipation. Third, the size of the expanded allele is not only inversely correlated with the age-of-onset of MJD (r = -0.738, p < 0.001), but is also correlated with the frequency of other clinical features [e.g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats (p < 0.001 and p < 0.05 respectively)]. Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD. Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.