Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation
Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation
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DOI：
10.1016/j.ajhg.2007.11.002
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发表时间：
2008-02-01
影响因子：
9.8
通讯作者：
Gecz, Jozef
中科院分区：
文献类型：
--
作者：
Froyen, Guy;Corbett, Mark;Gecz, Jozef
亚显微拷贝数失衡对人类疾病的遗传病因学有重要贡献。在这里，我们报告了一个新的微重复热点在Xp11.22确定在六个无关的家庭与主要非综合征XLMR。所有重复与疾病分离，包括大家族MRX17和MRX31。最小的，通常重复的区域包含三个基因：R1BC1，HSD17B10和HUWE1。RIBC1可以被排除在大脑中的表达的基础上，因为它逃脱了X失活的女性。对于其他基因，与对照相比，患者细胞系中的表达阵列和定量PCR分析显示，HSD17 B10和HUWE1以及其分子途径中的几个重要基因显著上调。HSD17 B10的功能缺失突变先前与进行性神经系统疾病和XLMR相关。E3泛素连接酶HUWE1与TP53相关的神经元细胞周期调控有关。在这里，我们还报告了分离的高度保守残基在HUWE1在三个XLMR家庭的序列变化，这些变化可能与表型。我们的研究结果表明，增加基因剂量的HSD17B10，HUWE1，或两者都有助于XLMR的病因，并建议在HUWE1点突变与这种疾病也。
Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: R1BC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.