Benko Sabina, Fantes Judy A, Amiel Jeanne, Kleinjan Dirk-Jan, Thomas Sophie, Ramsay Jacqueline, Jamshidi Negar, Essafi Abdelkader, Heaney Simon, Gordon Christopher T, McBride David, Golzio Christelle, Fisher Malcolm, Perry Paul, Abadie Véronique, Ayuso Carmen, Holder-Espinasse Muriel, Kilpatrick Nicky, Lees Melissa M, Picard Arnaud, Temple I Karen, Thomas Paul, Vazquez Marie-Paule, Vekemans Michel, Roest Crollius Hugues, Hastie Nicholas D, Munnich Arnold, Etchevers Heather C, Pelet Anna, Farlie Peter G, Fitzpatrick David R, Lyonnet Stanislas
INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
Nat Genet. 2009 Mar;41(3):359-64. doi: 10.1038/ng.329. Epub 2009 Feb 22.
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 approximately 1.5 Mb centromeric and approximately 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.
皮埃尔·罗宾序列（PRS）是腭裂的一个重要亚组。我们报告了几条证据，证明存在一个位于PRS之下的17q24基因座，包括连锁分析结果、在SOX9上游1.06 - 1.23 Mb处易位断点的聚集，以及在SOX9着丝粒方向约1.5 Mb和端粒方向约1.5 Mb处的微缺失。我们还在DNA的一个进化保守区域中鉴定出一个杂合点突变，该区域具有发育增强子的体外和体内特征。这个增强子位于断点簇的着丝粒方向，并且定位在其中一个微缺失区域内。与野生型序列相比，该突变消除了体外增强子功能，并改变了转录因子MSX1的结合。在发育中的小鼠下颌骨中，由微缺失界定的3-Mb区域在表达Sox9的细胞中显示出区域特异性的染色质解压缩。因此，一些PRS病例可能是由于超长距离顺式调控元件的破坏导致SOX9发育性表达异常所致。
