Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence
Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence
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DOI：
10.1038/ng.329
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发表时间：
2009-03-01
期刊：
影响因子：
30.8
通讯作者：
Lyonnet, Stanislas
中科院分区：
文献类型：
--
作者：
Benko, Sabina;Fantes, Judy A.;Lyonnet, Stanislas
Pierre Robin序列(PrS)是腭裂的一个重要亚型。我们报道了一些证据，证明了存在17q24基因座，包括连锁分析结果，SOX9上游1.06-1.23Mb易位断裂点的聚集，以及类似于SOX9的1.5Mb着丝粒和1.5Mb端粒的微缺失。我们还在一个进化保守的DNA区域发现了一个杂合点突变，具有发育增强子的体外和体内特征。该增强子是断裂点簇的着丝粒，并映射在一个微缺失区域内。与野生型序列相比，该突变取消了体外增强子功能，并改变了转录因子Msx1的结合。在发育中的小鼠下颌骨中，以微缺失为界的3-Mb区域在表达Sox9的细胞中显示出区域特异性的染色质分解。因此，一些PRS病例可能是由于SOX9的发育错误表达而导致的，这是由于极长范围的顺式调节元件的干扰。
Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both similar to 1.5 Mb centromeric and similar to 1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.