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.
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