Molecular and cellular mechanisms causing cleft lip/palate

项目摘要 唇裂伴或不伴腭裂（CLP）是男性最常见的出生缺陷之一， 全世界每700至1000名活产婴儿中有1人死亡。在过去几年中取得了相当大的进展 几十年来，确定了负责综合征形式的CLP和全基因组关联研究的基因 已经牵连许多基因组区域（和候选基因）的遗传贡献的非综合征 CLP。然而，对于相当一部分的唇裂病例，潜在的遗传基础仍然未知。在 此外，对裂缝基因功能的关注主要集中在少数转录调节因子和生长调节因子上。 这些因素已经被牵连，在很大程度上忽略了许多其他致病基因。他我们追求新的发现 来自两种已知的CLP蛋白，IRF 6和MID 1，这表明围绕直接的 唇形态发生过程中上皮细胞-细胞粘附的调节。该项目调查了新的 发现了这些蛋白质中的每一种都与负责协调动态过程的过程之间的联系。 细胞间粘附的行为与细胞骨架中的潜在变化复合， 最终促进唇的形态发生。此外，我们进一步支持以下方面的重要性： 通过调查可能致病的直接功能影响， 最近在一组患有非综合征型CLP的多代大家庭中发现的变异。的 该项目不仅突出了对CLP潜在分子机制的独特见解， 研究计划提供，但也有各种新颖的和国家的最先进的方法来追求的工作目标 了解这一常见出生缺陷的原因

Project Summary Cleft lip with or without cleft palate (CLP) is one of the most common birth defects in man with an incidence of between 1 in 700 and 1 in 1000 live births worldwide. Considerable progress has been made over the last few decades to determine the genes responsible for syndromic forms of CLP and genome-wide association studies have implicated many genomic regions (and candidate genes) in the genetic contribution to non-syndromic CLP. However, for a substantial fraction of cleft cases, the underlying genetic basis remains unknown. In addition, much of the focus on cleft gene functions has been on the few transcriptional regulators and growth factors that have been implicated, largely ignoring the many other causative genes. He we pursue new findings from two known CLP proteins, IRF6 and MID1, that suggest a convergence of function around the direct regulation of epithelial cell-cell adhesion during lip morphogenesis. The project investigates the newly discovered linkages that each of these proteins have with processes responsible for coordinating the dynamic behavior of intercellular adhesion complexes with the underlying changes in the cellular cytoskeleton that ultimately facilitate morphogenesis of the lip. In addition, we provide further support for the importance of components of this specific regulatory complex by investigating the direct functional impact of likely pathogenic variants recently discovered in a cohort of large multigenerational families with non-syndromic CLP. The project is highlighted not just by the unique insight into the molecular mechanisms underlying CLP that the research plan offers, but also the various novel and state-of-the-art approaches used to pursue the work aimed at understanding the causes of this common birth defect.