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

Meckel-Gruber 综合征的分子遗传学以及 meckelin 和 MKS1 的功能特征

• 批准号: G0700073/1
• 负责人: Colin Johnson
• 金额: $ 72.65万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700073%2F1
• 关键词: Molecular; genetics; Meckel; Gruber; syndrome

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.

神经管缺陷（NTD）发生在每1,000名新生儿中有1名，唇腭裂发生在每550名新生儿中有1名。NTD和裂缝问题是最常见的出生缺陷形式。NTD最常见的综合征形式是Meckel-Gruber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是由一个独特基因的变化引起的，该基因产生一种我们称为meckelin的大型新型蛋白质。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期间的行为。如果meckelin有缺陷或缺失，则该调节失效。Meckelin是初级纤毛的一种成分，初级纤毛是细胞的指状突起。纤毛被认为在神经管和其他管状结构的形成过程中检测和响应化学或机械线索，例如流体流动。我们的目标是更深入地了解胚胎发育过程中meckelin和纤毛中发现的其他蛋白质的分子作用，以及这些过程在人类疾病中是如何出错的。我们希望这项工作也将为复杂遗传疾病的原因提供关键的见解，包括脊柱裂和唇腭裂等NTD。