Neurogenetics Laboratory, Genetics and Molecular Pathology, SA Pathology at the Women's and Children's Hospital, Adelaide, South Australia, Australia.
Clin Genet. 2011 Dec;80(6):510-22. doi: 10.1111/j.1399-0004.2011.01685.x. Epub 2011 May 18.
ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)(7)'expansion' of pA1 and c.429_452dup 'dup24bp' of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G>T). Four ultraconserved regions distal to ARX (uc466-469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation.
ARX 突变导致了广泛的人类疾病谱,从严重的脑和生殖器畸形到非综合征性智力障碍(ID)。ARX 是一种具有多个结构域的转录因子,包括四个多聚丙氨酸(pA)结构域,其中前两个结构域经常因突变而扩展。我们逐步筛查了最初来自 613 名 ID 患者的 DNA 样本,这些患者的 ARX 最常见突变(c.304ins(GCG)(7)'扩增'pA1 和 c.429_452dup 'dup24bp'pA2)。对没有 pA1 或 pA2 突变的 500 个样本,我们通过单链多态性构象(SSCP)和/或变性高压液相色谱(dHPLC)分析筛选了整个 ARX ORF。总的来说,在 ARX 中发现了六个突变的八个家族(1.31%):pA2 中的五个重复突变(0.82%),其中三个新的家族报告了带有 dup24bp 的病例,还有两个大于 dup24bp 突变的重复(dup27bp、dup33bp);以及三个点突变(0.6%),包括在同源域中发现的一个新突变(c.1074G>T)。在 94 名患者的亚组中还筛查了 ARX 远端的四个超保守区(uc466-469),在两个患者中发现了三个独特的核苷酸变化(uc466、uc467)。对 11 种变体的全长 ARX 蛋白的亚细胞定位进行了评估。正如之前在 pA1 中所提出的,pA2 结构域长度和表型严重程度的增加导致蛋白质定位错误。同样,同源域突变的蛋白质定位错误也与临床严重程度相关,表明一种新的基因型与细胞表型相关性正在出现。