Molecular genetics of Meckel-Gruber syndrome, and functional characterization of meckelin and MKS1

神经管缺陷（NTDs）发生率为千分之一，唇腭裂发生率为550分之一。NTDs和唇裂问题是最常见的出生缺陷。NTD最常见的综合征形式是梅克尔-格鲁伯综合征（MKS），这是一种遗传性疾病，在胚胎发育期间出现脑、肝和肾缺陷。此外，唇腭裂是MKS的常见临床特征。最近，我们发现MKS是由一种独特基因的变化引起的，这种基因产生了一种巨大的新型蛋白质，我们称之为meckelin。Meckelin将发育信号从细胞外部传递到细胞内部，控制细胞在胚胎发育过程中的行为。如果meckelin有缺陷或缺失，则该规则丢失。麦毛蛋白是初级纤毛的组成部分，初级纤毛是从细胞中伸出的手指状突起。纤毛被认为是在神经管和其他管状结构形成过程中检测并响应化学或机械信号，如流体流动。我们的目标是更深入地了解胚胎发育过程中纤毛中发现的meckelin和其他蛋白质的分子作用，以及这些过程如何在人类疾病中出错。我们希望这项工作还将为复杂遗传疾病的病因提供关键见解，包括脊柱裂、唇腭裂等被忽视的疾病。

Neural tube defects (NTDs) occur in 1 per 1,000 births, and cleft lip and palate occurs in 1 per 550 births. NTDs and clefting problems are the most common forms of birth defect. The most common syndromic form of NTD is Meckel-Gruber syndrome (MKS) which is an inherited condition with brain, liver and kidney defects that arise during embryonic development. In addition, cleft lip and palate is a common clinical feature of MKS. Recently, we found that MKS is caused by changes in a unique gene that makes a large, novel protein that we have called meckelin. Meckelin carries developmental signals from the outside to the inside of a cell, controlling how the cell will behave during embryonic development. This regulation is lost if meckelin is defective or absent. Meckelin is a component of primary cilia, which are finger-like projections from cells. Cilia are thought to detect and respond to chemical or mechanical cues, such as fluid flow, during the formation of the neural tube and other tubular structures. We aim to have a deeper understanding of the molecular roles of meckelin and other proteins found at cilia during embryonic development, and how these processes go wrong in human diseases. We hope that the work will also provide key insights into the causes of complex genetic diseases, including NTDs such as spina bifida, and cleft lip and palate.