Molecular Analysis of Alagille Syndrome

描述（由申请人提供）：疾病基因的鉴定是理解遗传性疾病病因的第一步。了解导致和改变临床表型的遗传因素，可以提供对疾病机制的发展洞察，并导致更好的诊断和对携带这些疾病基因的家庭的咨询。Alagille综合征是一种显性遗传性遗传疾病，可导致肝脏、心脏、眼骨骼和面部发育异常。这种疾病的表现力是高度可变的，无论是在家庭内部还是家庭之间。AGS是由Jaggedi（JAGI）突变引起的，JAGI是进化上保守的Notch信号通路的成员。在60-70%的临床诊断为AGS的患者中可以鉴定出JAGI突变。大多数突变是蛋白质截短，但总基因缺失，剪接和错义突变都已被确定。迄今为止研究的所有突变似乎导致JAG 1的单倍不足，包括错义突变，已发现其导致蛋白质产物不能到达细胞表面。对于大多数发现家族内变异的疾病（包括AGS），不能得出基因型-表型相关性。在这些情况下，可能涉及遗传修饰因子的存在。 目前的建议旨在扩展我们以前的工作，并解决以下问题：1）与JAG 1突变相关的临床表现范围是什么？2)我们能否在30-40%未发现突变的患者中识别出突变？3)错义突变导致无功能蛋白的机制是什么？这些突变告诉我们Notch受体-配体信号传导的正常机制是什么？是否有错义突变证明了基因型-表型相关性？4)哪些因素改变了疾病的表现力？疾病基因变异是由JAG 1自身的多态性引起的吗？在Notch 2？还是Notch信号通路的其他成员5)对小鼠突变体的遗传分析能否揭示修饰AGS表型的候选基因？我们建议开展的工作将对Alagille综合征家庭的诊断和咨询产生直接影响。

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.