RbFox Genes in Congenital Heart Disease and Cardiomyopathy
Abstract
Hypoplastic left heart syndrome (HLHS) is a devastating form of congenital heart disease (CHD) that is caused by underdevelopment of the left side of the heart. Whole exome sequencing identified mutations in the RNA splicing factor Rbfox2 that segregate with HLHS in newborns. While these mutations are likely to be causal, this hypothesis has yet to be tested. Moreover, Rbfox2 has not been linked previously to cardiac development. As such, its mechanism of action is unknown. We created the first clinically relevant zebrafish model of HLHS by mutating the rbfox orthologs, rbfox11 and rbfox2. Specifically, we found that Rbfox double mutant embryos die within 4 days of life from severe cardiovascular abnormalities that mirror HLHS in newborns. While heart development is normal in single mutant zebrafish, progressive heart failure develops in Rbfox2 adults that is lethal by 5 months of age, implicating Rbfox2 as a risk factor for early onset cardiomyopathy. We propose to exploit our unique system over three years to gain new mechanistic insights into the roles of Rbfox in developing and maintaining the heart. In Aim 1, we will study the cardiovascular defects in Rbfox double mutant embryos in more detail and distinguish primary from secondary malformations. In Aim 2, we will study the heart failure observed in Rbfox2 mutant adults. In Aim 3, we will discover the molecular targets of Rbfox to learn how mutations in this gene lead to cardiovascular defects in both our HLHS embryonic model and our adult heart failure model.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2022
- Accession Number
- AD1170072
Entities
People
- Caroline E Burns