Sequence Analysis of 5' Regulatory Regions of the Machado-Joseph Disease Gene (ATXN3)
Sequence Analysis of 5' Regulatory Regions of the Machado-Joseph Disease Gene (ATXN3)
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DOI：
10.1007/s12311-012-0373-7
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发表时间：
2012-12-01
期刊：
影响因子：
3.5
通讯作者：
Lima, Manuela
中科院分区：
文献类型：
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作者：
Bettencourt, Conceicao;Raposo, Mafalda;Lima, Manuela
马查多-约瑟夫病 (MJD) 是一种迟发性常染色体显性神经退行性疾病，由 ATXN3 基因 (14q32.1) 的编码 (CAG)(n) 扩展引起。扩展等位基因中的 CAG 重复次数仅占起始变异的 50% 至 75%，其余变异取决于其他因素。 ATXN3 的差异等位基因表达可能有助于解释具有相似 CAG 重复大小的患者的不同发病年龄。 ATXN3 基因 5' 调控区的变异可能会影响表达水平，并最终调节 MJD 表型。这项工作的主要目标是分析 ATXN3 起始密码子上游序列变异的程度。对 186 名患者和 59 名对照者（490 条染色体）中包含核心启动子和 5' 非翻译区 (UTR) 的片段进行了测序和分析。在核心启动子中，没有观察到多态性。在 5'UTR 中，仅发现了一个 SNP (rs3814834)，但当在线性模型中添加其等位基因状态时，没有观察到起始方差解释的改进。因此，计算机分析预测该 SNP 位于 CMYB 结合的非保守位置。因此，无法预测该变体的功能效应。
Machado-Joseph disease (MJD) is a late-onset autosomal dominant neurodegenerative disorder, which is caused by a coding (CAG)(n) expansion in the ATXN3 gene (14q32.1). The number of CAG repeats in the expanded alleles accounts only for 50 to 75 % of onset variance, the remaining variation being dependent on other factors. Differential allelic expression of ATXN3 could contribute to the explanation of different ages at onset in patients displaying similar CAG repeat sizes. Variation in 5' regulatory regions of the ATXN3 gene may have the potential to influence expression levels and, ultimately, modulate the MJD phenotype. The main goal of this work was to analyze the extent of sequence variation upstream of the ATXN3 start codon. A fragment containing the core promoter and the 5' untranslated region (UTR) was sequenced and analyzed in 186 patients and 59 controls (490 chromosomes). In the core promoter, no polymorphisms were observed. In the 5' UTR, only one SNP (rs3814834) was found, but no improvements on the explanation of onset variance were observed, when adding its allelic state in a linear model. Accordingly, in silico analysis predicted that this SNP lays in a nonconserved position for CMYB binding. Therefore, no functional effect could be predicted for this variant.