Identification of genes causing human disease provides insight into the molecular pathways involved in normal and abnormal human development. We have recently identified Jagged1 (JAG1) as the disease gene causing Alagille syndrome, a genetic disorder associated with heart, liver and several other anomalies. JAG1 is a ligand in the Notch Signaling pathway, shown in multiple organisms to be involved in cell fate determination. Alagille syndrome is a dominant disorder, with extreme variability in the expression of phenotypic features. Some individuals with JAG1 mutations have only a single clinical feature, rather than the multisystem involvement characteristic of Alagille syndrome. We will study the families of a large cohort of patients with Alagille syndrome both clinically and at the molecular level to determine the complete range of clinical features associated with mutations in JAG1 and to determine the phenotypic effects of a JAG1 mutation; i.e.; what percentage of mutation carriers have clinically significant disease. Given the known clinical variability of features of Alagille syndrome in family members of patients, we have hypothesized that JAG1 mutations will be identified in individuals with isolated heart disease and we have preliminary data to support this hypothesis. We propose to extend this work to study a cohort of patients who have cardiac disease of the types most commonly seen in Alagille syndrome (peripheral pulmonic stenosis, pulmonic stenosis and tetralogy of Fallot) to determine the frequency of JAG1 mutations associated with these cardiac defects. Furthermore, we propose that mutations in other members of the Notch signaling pathway may be associated with cardiac abnormalities. Delta and SMRT are two genes we propose to study. The Notch ligand Delta has recently been mapped to 6q27, a region of the genome associated with cardiac disease in patients deleted for this region. We will determine if Delta is responsible for a subset of cardiac disease, of the type seen in patients with 6q deletions. We have recently mapped SMRT, a transcriptional co-repressor which has been shown to function downstream of Notch, to 12q24, close to the previously identified critical region for Noonan syndrome, another dominant disorder associated with cardiac disease (in addition to other anomalies). This gene will be tested as a candidate gene for this (Noonan syndrome) disorder.
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