Molecular Analysis of Alagille Syndrome

描述（由申请人提供）：疾病基因的鉴定是了解遗传病病因学的第一步。了解引起和改变临床表型的遗传因素可以提供对疾病机制的发育洞察，并有助于更好地诊断和咨询携带这些疾病基因的家庭。Alagille综合征是一种遗传性疾病，会导致肝脏、心脏、眼睛、骨骼和面部发育异常。这种疾病的表现在家庭内部和家庭之间都是高度可变的。AGS是由Jaggedi （JAGI）突变引起的，JAGI是进化保守的Notch信号通路的一员。在60-70%临床诊断为AGS的患者中可发现JAGI突变。大多数突变是蛋白质截短，但全基因缺失、剪接和错义突变都已被发现。迄今为止研究的所有突变似乎都导致JAG1的单倍体不足，包括错义突变，已发现错义突变导致蛋白质产物无法到达细胞表面。对于大多数发现家族内变异的疾病（包括AGS），无法绘制基因型-表型相关性。在这些情况下，可能涉及到基因修饰因素的存在。

DESCRIPTION (provided by applicant): The identification of disease genes is one of the first steps towards understanding the etiology of genetic diseases. Understanding the genetic factors that cause and modify clinical phenotypes provides developmental insight into the mechanisms of the disorder and leads to better diagnosis and counseling of families that harbor these disease genes. Alagille syndrome is a dominantly inherited genetic disease that results in developmental abnormalities of the liver, heart, eye skeleton and face. The expressivity of this disorder is highly variable, both within and between families. AGS is caused by mutations in Jaggedi (JAGI), a member of the evolutionarily conserved Notch signaling pathway. JAGI mutations can be identified in 60-70% of patients with clinically diagnosed AGS. Most mutations are protein truncating, but total gene deletions, splicing and missense mutations have all been identified. All mutations studied to date appear to result in haploinsufficiency for JAG1, including missense mutations, which have been found to result in a protein product that does not reach the cell surface. For the majority of disorders in which intrafamilial variation is found (including AGS), genotype-phenotype correlations cannot be drawn. In these cases the presence of genetic modifying factors may be implicated. The current proposal aims to extend our previous work and address the following questions: 1) What is the range of clinical manifestations associated with a JAG1 mutations? 2) Can we identify mutations in the 30-40% of patients in whom a mutation has not been found? 3) What is the mechanism by which the missense mutations lead to a non-functional protein and what do these mutations tell us about the normal mechanisms for Notch receptor-ligand signaling? Are there missense mutations that demonstrate a genotype-phenotype correlations? 4) What factors modify disease expressivity? Is disease gene variability caused by polymorphisms in JAG1 itself? in Notch2? or in other members of the Notch signaling pathway? 5) Can genetic analysis of mouse mutants reveal genes that are candidates for modifying the AGS phenotype? The work we propose to carry out will have direct implications for diagnosis and counseling of families with Alagille syndrome.