Identification of genes causing human cardiac disease provides insight into the molecular pathways involved in heart development. The investigators 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 multi- system involvement characteristic of Alagille syndrome, which led the investigators to hypothesize that JAG1 mutations would be identified in patients with isolated heart disease. The preliminary data support this hypothesis, as the investigators have identified three patients with cardiac disease and JAG1 mutations who do not manifest the liver abnormalities associated with Alagille syndrome. The investigators will extend this work to study a cohort of patients to determine the frequency of JAG1 mutations associated with cardiac defects. In order to understand how JAG1 is involved in cardiovascular development, the investigators will analyze location and timing of JAG1 expression in the developing mouse embryo. The investigators will also address the mechanism by which mutations in JAG1 cause heart disease. In Drosophila, mutations in Notch ligands which cause truncated proteins similar to those predicted in Alagille syndrome patients, act in a dominant negative fashion. However, there is compelling data from human studies that the mechanism for the effect of JAG1 is haploinsufficiency. The investigators propose to overexpress the mutations seen in Alagille syndrome patients in the mouse embryo and determine their effect on early vascular development. The investigators further propose that other members of the Notch signaling pathway may be associated with cardiac abnormalities. 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. The investigators will determine if Delta is the gene responsible for heart disease in these patients. If they are unable to show a role for Delta, they will use a positional cloning approach to identify other gene(s) associated with cardiac disease from 6q27. In summary, this work will provide an increased understanding of the role of JAG1 in normal and abnormal development of the heart, and lay the foundation for identifying additional genes contributing to cardiac disease.
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