Abstract
Left-sided congenital heart defects (CHDs) are among the most common forms of congenital heart disease, but a disease-causing gene has only been identified in a minority of cases. Here, we identified a candidate gene for CHDs, KIF1A, that was associated with a chromosomal balanced translocation t(2;8)(q37;p11) in a patient with left-sided heart and aortic valve defects. The breakpoint was in the 5′ untranslated region of the KIF1A gene at 2q37, which suggested that the break affected the levels of Kif1A gene expression. Transgenic fly lines overexpressing Kif1A specifically in the heart muscle (or all muscles) caused diminished cardiac contractility, myofibrillar disorganization, and heart valve defects, whereas cardiac knockdown had no effect on heart structure or function. Overexpression of Kif1A also caused increased collagen IV deposition in the fibrous network that normally surrounds the fly heart. Kif1A overexpression in C2C12 myoblasts resulted in specific displacement of the F-actin fibers, probably through a direct interaction with G-actin. These results point to a Kif1A-mediated disruption of F-actin organization as a potential mechanism for the pathogenesis in at least some human CHDs.
Highlights
Congenital heart defects are the most common birth defect, occurring in about 0.7% of all newborn infants [1]
The ratio of cell area per nucleus was the same for both GFP and Kif1A-transfected cells. These results suggest that overexpression of Kif1A impairs myocyte maturation, likely through disruption of actin organization, which is consistent with the effects of Kif1A overexpression in the fly heart
We identify the Kif1A gene as a candidate gene for causing left-sided heart defects and utilize Drosophila to demonstrate the pathologic effects of overexpression of the Kif1A gene on heart development and function
Summary
Congenital heart defects are the most common birth defect, occurring in about 0.7% of all newborn infants [1]. HLHS may represent a severe neonatal form of cardiomyopathy, suggesting an underlying defect in cardiac myocyte development Consistent with this model, histopathologic analysis of left ventricular myocardial tissue from explanted HLHS infant hearts revealed fibrosis and myocyte disarray [5], as observed in some forms of cardiomyopathy, it is possible that these changes arise secondarily to impaired hemodynamics. Mutations in the cardiac transcription factor NKX2.5 have been observed in patients with HLHS [6] and in other patients with hypertrophic cardiomyopathy (HCM) [7], suggesting that HLHS and HCM could represent different forms of cardiomyopathy along a common disease spectrum In this case, it is possible that multiple developmental pathways are affected that cause primary valve and myocardial defects through a “multi-hit” mechanism (either through a single or multiple affected genes) and that additional genetic and/or epigenetic factors can influence the severity of the phenotype
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