INSERM, U955, Equipe11, Hôpital Henri Mondor, Créteil, France.
Eur J Hum Genet. 2012 Sep;20(9):990-4. doi: 10.1038/ejhg.2012.29. Epub 2012 Feb 29.
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.
瓦登伯格综合征 4 型（WS4）是一种罕见的神经嵴疾病，其特征是瓦登伯格综合征（感觉神经性听力损失和色素沉着缺陷）和先天性巨结肠（肠无神经节细胞症）的组合。已知有三个基因与该综合征有关，即 EDN3（内皮素 3）、EDNRB（内皮素受体 B）和 SOX10。然而，15-35%的 WS4 在分子水平上仍无法解释，这表明可能涉及其他基因，或者已知基因中的突变可能逃脱了先前的筛查。在这里，我们在最近确定的 SOX10 调控序列中搜索缺失，并描述了首例表现为包含三个增强子的大片段缺失的 WS4 患者的特征。对断裂点区域的分析表明，涉及三个 Alu 序列的复杂重排，这可能是由 FosTes/MMBIR 复制机制介导的。结合最近的报告，我们的结果表明，位于关键基因的编码序列内或远处的高度保守的非编码元件的破坏会导致多种神经嵴疾病。这为神经嵴疾病的分子剖析开辟了新途径。
