Congenital heart disease is one of the major causes of infant mortality and morbidity in the US. However, we know little about the genetic causes of this disease. In order to better understand congenital heart disease, we analyzed the human genetics of cardiac malformations. In particular, we studied heterotaxy patients with congenital heart disease for copy number variations. Heterotaxy is a disorder of left-right patterning and alters cardiac development due to failure of cardiac looping morphogenesis. In a heterotaxy patient, we identified duplication in the NUP188 gene, which encodes a component of the nuclear pore complex known as a nucleoporin. We then modeled this cardiovascular disease in Xenopus by knocking down nup188, which recapitulated the human heterotaxy phenotype. The main goal of this proposal is to analyze the role of nucleoporins in left-right patterning and congenital heart disease. Our preliminary data suggest that nucleoporins are important for cilia. Cilia are critical regulators of left-right patterning and so loss of cilia could explain the left-ight phenotype. In this proposal, we have three main aims: 1) Analyze multiple nucleoporins to see if they also alter left-right patterning and cilia 2) use super-resolution imaging to define the structure of nucleoporins at the base of the cilium and 3) determine the mechanism by which nucleoporins contribute to the function of cilia.

Public Health Relevance

In the US, the most common cause of death in infants is birth defects, and chief among these is congenital heart disease, or 'holes in the heart.' The genetic basis for congenital heart disease is not well established, but our interdisciplinary team of physicians and basic cell biologists promises to shed light on at least one potential cause. Our hope is to provide patients and parents with a better understanding of the disease, genetic counseling, and to improve the long-term outcome of these patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Schramm, Charlene A
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Yale University
Schools of Medicine
New Haven
United States
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