Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses. CHDs that present with defective ventricular morphogenesis allow for the mixing of oxygenated and deoxygenated blood via ventricular septal defects (VSDs) and/or impaired contractile function both of which put limits on vitality. Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many forms of ventricular CHDs. Hand1 is expressed within the developing left ventricle (LV) myocardium and the myocardial cuff (MC) between embryonic day (E) E8.5 and E13.5. Gene targeting models establish that Hand1 is required for normal LV development. We show that cardiomyocyte deletion of Hand1 results in surviving mice that present with CHDs effecting LV morphology. Recently, HAND1 mutations have been identified in patients diagnosed with CHDs. These HAND1 gene mutations manifest as frameshift or nonsense mutations within the protein coding domains and are reported to be somatic in nature, as germline mutations in HAND1 are assumed to be embryonic lethal. Like all genes, Hand1 is transcriptionally regulated through cis-element enhancers located within Conserved Non-coding Sequences (CNS) that are present both 5' and 3' to the Hand1 transcriptional start site. The notion that CNS gene mutations affecting the function of Hand1 through defects in cardiac transcriptional regulatory elements is a largely unexplored hypothesis that could provide a mechanism for heritable Hand1 cardiac loss-of-function in human CHDs.
CHDs resulting in ventricle phenotypes have the poorest clinical outcomes. Thus, gaining an understanding of the etiology and molecular mechanisms that cause CHDs resulting in altered ventricular morphogenesis has the potential to benefit thousands of pediatric patients annually. Hand1 plays a key role in cardiomyocyte patterning and gaining insight into the cellular and molecular mechanism of this understudied developmental process will have a great benefit to developing non-surgical treatments for CHD patients.
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