Investigators:
- Vicky L. Funanage, PhD
- Robert E. Akins, PhD
- Christian Pizarro, MD
Background
Congenital heart malformations are the most common birth defect and remain the leading cause of death in infancy. One of the most serious malformations is hypoplastic left heart syndrome (HLHS), which is universally fatal without surgical intervention and occurs in 2.4 of every 10,000 live births. The genetic and environmental factors that lead to congenital heart defects like HLHS are not understood. However, several transcription factors have been recently identified that are expressed early in heart development. One such transcription factor, TBX5, has been shown to be the cause of heart malformations in humans. Expression of the TBX5 gene occurs throughout the cardiac crescent, and as the heart develops, is restricted to the atria, left ventricle and outflow tract of the heart. We hypothesize that HLHS results from defects in the TBX5 gene.
What We're Doing
We are currently investigating the expression of TBX5 in babies diagnosed with HLHS and those born with other cardiac malformations. We are testing DNA from these children and their parents for common genetic problems within the TBX5 gene. Secondly, we are testing this same gene in tissue samples obtained from babies undergoing cardiac procedures for HLHS. Other important cardiac transcription factors, such as NKX2.5 and GATA4, are also being analyzed in our cardiac patient population.
Some of What We've Found
We have found mutations and/or polymorphisms of the TBX5 gene in the majority of HLHS patients analyzed. We are currently determining whether any of these mutations alter the ability of TBX5 to bind to DNA and activate transcription. For mutations that alter the transcriptional activity of TBX5, we plan to create mouse models in which to test the effect of these mutations on cardiac development. These mouse models of HLHS will be useful for screening therapeutic agents and understanding post-surgical complications that influence the survival of HLHS infants. Additionally, we will gain an understanding of the role of TBX5 in cardiac development and function, thus providing insight into later complications that may occur in the HLHS heart. Finally, we have identified single nucleotide polymorphisms (SNPs) in both the TBX5 and NKX2.5 genes that may prove useful for linkage analysis of HLHS and other congenital heart malformations.