Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4
Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4
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DOI：
10.1038/ejhg.2012.29
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发表时间：
2012-09-01
影响因子：
5.2
通讯作者：
Pingault, Veronique
中科院分区：
文献类型：
--
作者：
Bondurand, Nadege;Fouquet, Virginie;Pingault, Veronique
Waardenburg综合征4型（WS4）是一种罕见的神经嵴疾病，由Waardenburg综合征（感音神经性听力损失和色素沉着缺陷）和先天性巨结肠症（肠无神经节细胞症）的组合定义。已知有三种基因参与该综合征，即EDN 3（内皮素-3）、EDNRB（内皮素受体B型）和SOX 10。然而，仍有15 - 35%的WS4在分子水平上无法解释，这表明可能涉及其他基因和/或已知基因内的突变可能逃过了先前的筛查。在这里，我们搜索最近确定的SOX 10调控序列中的缺失，并描述了WS4患者的第一个特征，该患者存在包含三个增强子的大缺失。断点区域的分析表明，涉及三个Alu序列，可以介导的FosTes/MMBIR复制机制的复杂重排。结合最近的报道，我们的研究结果表明，位于关键基因编码序列内或距离编码序列较远的高度保守的非编码元件的破坏可导致几种神经损伤。这为神经嵴疾病的分子解剖开辟了新的途径。European Journal of Human Genetics（2012）20，990 - 994; doi：10.1038/ejhg.2012.29; 2012年2月29日在线发表
Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders. European Journal of Human Genetics (2012) 20, 990-994; doi:10.1038/ejhg.2012.29; published online 29 February 2012