Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development
Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development
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DOI：
10.1016/j.ajhg.2013.11.009
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发表时间：
2014-01-02
影响因子：
9.8
通讯作者：
Schutte, Brian C.
中科院分区：
文献类型：
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作者：
Peyrard-Janvid, Myriam;Leslie, Elizabeth J.;Schutte, Brian C.
干扰素调节因子6 （IRF6）的突变导致了大约70%的Van der Woude综合征（VWS），这是唇腭裂最常见的综合征形式。在45个缺乏IRF6突变的vws影响家族中，有8个家族发现GRHL3编码突变。根据一项基于斑马鱼的实验，与疾病相关的GRHL3突变破坏了外周发育，并具有显性负作用，这与大多数由IRF6突变引起的VWS病例的单倍功能不全形成了鲜明对比。在小鼠中，所有缺乏Grhl3的胚胎都表现出口腔外周异常，17%的胚胎发生腭裂。双杂合子Irf6（+/-）口腔表型分析Grhl3(+/-))小鼠胚胎未能检测到这两个基因之间的上位性，这表明它们在发育过程中以不同但趋同的途径发挥作用。综上所述，我们的数据表明，IRF6和GRHL3这两个基因的突变可以导致几乎相同的口面裂表型。他们支持这样的假设，即这两个基因对于口腔外周功能的存在是必不可少的，而这一过程的失败导致了VWS。
Mutations in interferon regulatory factor 6 (IRF6) account for similar to 70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.