Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis caused by mutations in ADAR1 . In this study, we performed mutation analysis on a family that included typical DSH patients. No mutations were found in any coding regions or exon–intron boundary regions of ADAR1 , but a previously unreported non‐coding heterozygous variant, c.‐60A>G, was found in the 5′ untranslated region (5′UTR) of ADAR1 in the proband and her mother. The function of 5′UTR in mRNA is not well‐understood. To understand the pathogenesis of the variant and the function of the 5′UTR of ADAR1 , we constructed two reporter genes carrying the ADAR1 5′UTR sequence with/without the variant between the PGK promoter and a luciferase coding sequence, and performed luciferase assays, semi‐quantitative PCR analyses, and polysomal assays. In human melanocytes, c.‐60A>G induced a 16% reduction in transcription and a 51% reduction in translation. Our results indicate that the 5′UTR c.‐60A>G variant adversely affects the post‐transcriptional step in gene expression, leading to DSH. Detailed functional assays of the 5′UTR of ADAR1 in the present study revealed the gene expression to be not only downregulated, but also upregulated by defects in 5′UTR depending on the locations. The regulation of translation by 5′UTR is very complicated.

中文翻译：

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对称性色素异常病ADAR1 5'非翻译区变异的发病机理。

对称性色素沉着症（DSH）是由ADAR1突变引起的色素性皮肤病。在这项研究中，我们对包括典型DSH患者的家庭进行了突变分析。无突变在任何编码区或外显子-内含子的边界区域被发现ADAR1，但以前未报告的非编码杂合变体，C.-60A> G，在5'非翻译区（5'UTR）中发现ADAR1在先证者和她的母亲。5'UTR在mRNA中的功能尚未被很好地理解。为了了解ADAR1变异的发病机理和5'UTR的功能，我们构建了两个携带ADAR1的报告基因。PGK启动子和荧光素酶编码序列之间有/无变异的5'UTR序列，并进行了荧光素酶测定，半定量PCR分析和多体测定。在人类黑素细胞中，c.-60A> G导致转录减少16％，翻译减少51％。我们的结果表明5'UTR c.-60A> G变体会对基因表达的转录后步骤产生不利影响，从而导致DSH。在本研究中，对ADAR1的5'UTR进行的详细功能分析表明，基因表达不仅受到下调，而且受位置的5'UTR中的缺陷上调。5'UTR对翻译的调控非常复杂。