Genetic Impact of MYH6 Variants in Congenital Heart Disease

Improving understanding of Hypoplastic Left Heart Syndrome

Full Project Name:Genetic Impact of MYH6 Variants in a Patient-Derived In Vitro Model of Congenital Heart DiseasePrinciple Investigator:Michael E. Mitchell, MD, SurgeryCo-Investigator:Aoy T. Mitchell, PhD, SurgeryAward Amount:$200,000
Award Date
February2017
Project Duration:24 months

Project Description Narrative:


Congenital heart disease is the most common severe birth defect and the second most frequent cause of childhood death. In Wisconsin, an average of 748 babies are born with a heart defect each year. Hypoplastic Left Heart Syndrome (HLHS), a severe form of congenital heart disease, is responsible for approximately 20% of congenital heart disease related mortality. HLHS is likely genetic in origin, however its cause remains unknown. By developing a better understanding of the cause of HLHS, better therapies may be developed to increase survival from this deadly form of congenital heart disease.

Through this award, researchers will seek to advance understanding of normal and abnormal cardiac development and function, enable risk stratification and precision medicine for HLHS patients, and improve techniques to generate bioengineered tissue for surgical repair.

Project Updates:


• Examined slides of atrial septal tissues from CHD patients with and without MYH6 variants, observing differences in sarcomere organization in variant carriers; examined slides from ventricular tissues and observed that the differences appeared to be atrial tissue specific, as differences were not observed in ventricular tissue from the same patients

• Demonstrated that introducing a MYH6 R443P variant using CRISPR/Cas9 technology into stem cells affects sarcomere organization/creates a cellular phenotype; initiated studies on apoptosis and proliferation studies in these cell lines; initiated contractility studies

• Learned that the MYH6 gene affects sarcomeres of atrial tissue and introduction of patient-specific variants recapitulate the sarcomere phenotype. These results are likely to advance knowledge for the rational application of precision medicine

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