Hypoplastic Left Heart Syndrome: Molecular Consequences of Transcriptions Factor Mutations
Date
2012-05
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Publisher
University of Delaware
Abstract
Hypoplastic left heart syndrome (HLHS) is a congenital disorder affecting the left side of the heart. It is characterized by an underdeveloped left ventricle, an atrial septal defect, a narrowed aorta, and an open ductus arteriosus. Children diagnosed with HLHS generally present with cardiogenic shock, such as arrhythmia, cardiac arrest, or congestive heart failure, and are likely to die without surgical intervention. To improve diagnostic options, an understanding of the etiology of HLHS is needed. A genetic linkage to HLHS has been proposed; unfortunately, little evidence exists to support this hypothesis, as the mechanisms of cardiogenesis are only partially known. However, Holt-Oram Syndrome (HOS), a congenital disorder of heart and hand development, can present with HLHS as a symptom and has been linked to a T-box transcription factor involved in cardiac development, TBX5. Other studies have reported families with atrial septal defects, a symptom of HLHS, to carry mutations in NKX2.5, another transcription factor involved in cardiogenesis. This study hypothesized, based on previous findings, that mutations in TBX5, NKX2.5 or another co-transcription factor involved in cardiogenesis contribute to the etiology of HLHS. To examine the mutational status of TBX5 and NKX2.5 in patients with HLHS, venous blood and atrial appendage tissue were collected for DNA isolation and polymerase chain reaction amplification of the region of interest. Genomic DNA sequencing of TBX5 revealed an interesting combination of 11 synonymous, non-synonymous, and intronic variations among 19 probands out of 110 screened. The non-synonymous variations were all in exon 8. NKX2.5 showed one variation in one proband out of 110. Computer analyses determined the probability of pathogenicity of each variation but further in vitro/in vivo studies need to be conducted to more clearly determine the effect of these variations on cardiac development. The possible correlation between genotype and phenotype could help further the understanding of the molecular mechanisms behind cardiac and HLHS development.