Atrioventricular defects (AVSDs) are complex heart malformations found in 5% of patients with congenital heart disease (CHD). They are particularly prevalent in patients with genetic disorders such as Down Syndrome, and CHARGE Syndrome. There are two major types of AVSDs. Partial (or incomplete) AVSDs and complete AVSDs. The partial AVSDs are characterized by the presence of a primary atrial septal defects (pASDs) and a common AV valves (cAVVs), while in complete AVSDs, in addition to these two abnormalities, ventricular septal defects (VSDs) are also found. The nature of an AVSD has a significant implication for postnatal treatment. Patients born with complete AVSDs will typically have to undergo surgery within the first months of life to prevent the development of pulmonary hypertension, whereas asymptomatic patients with partial AVSDs, may receive surgery later in life. Individuals with a surgically repaired AVSD may, at one point, require re-operation to address, for instance, valve insufficiency or pacemaker implantation, or to deal with other conditions that interfere with proper heart function as they get older. For many years it was believed that AVSDs were caused by failure of the endocardially-derived AV cushions to develop properly. This belief led to the introduction and use of the term ?endocardial cushion defect?. Studies conducted in our lab on the role of the Dorsal Mesenchymal Protrusion (DMP) in heart development have, however, significantly shifted this paradigm. The DMP is a Second Heart Field (SHF)-derived mesenchymal structure located at the venous pole of the heart. Together with the AV cushions and the mesenchymal cap on the primary atrial septum, the DMP forms the AV mesenchymal complex. We have recently begun to explore the role of Sox9 in AVSD pathogenesis. Importantly, we found that deletion of Sox9 from the SHF and from the endocardial lineage both result in complete AVSD. This result has prompted us to revisit, the current paradigm for the pathogenesis of AVSDs. In this project we will explore the role of Sox9 in the development of each of the mesenchymal structures that contribute to the AV mesenchymal complex and test the hypothesis in the pSHF, Sox9 is a common downstream target and regulator for signaling pathways proven to be critical for development of the DMP. We will also test the hypothesis that chromosome-helicase- DNA-binding protein 7 (Chd7), the gene frequently found to be mutated in patients with CHARGE syndrome and expressed in the pSHF, is involved in DMP development and AV septation by controlling pSHF proliferation and by regulating Sox9 expression and p53 activation.

Public Health Relevance

Atrioventricular defects (AVSDs) are complex heart malformations found in 5% of the total population of patients with congenital heart disease (CHD) and are particularly prevalent in genetic disorders including Down Syndrome and CHARGE Syndrome. Elucidating the molecular and cellular mechanisms underlying the pathogenesis of AVSDs could lead to strategies to prevent and/or treat this congenital defect.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Schramm, Charlene A
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Medical University of South Carolina
Anatomy/Cell Biology
Schools of Medicine
United States
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Burns, Tara; Yang, Yanping; Hiriart, Emilye et al. (2016) The Dorsal Mesenchymal Protrusion and the Pathogenesis of Atrioventricular Septal Defects. J Cardiovasc Dev Dis 3:
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