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Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated
David Y Barefield1, Megan J Puckelwartz1, Ellis Y Kim1
1From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (D.Y.B., M.J.P., J.U.E., M.H., L.D.-C., E.M.M.); Molecular Pathogenesis and Molecular Medicine, University of Chicago, IL (E.Y.K.); Feinberg Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (L.D.W.); Committee on Development, Regeneration and Stem Cell Biology, University of Chicago, IL (A.H.V.); Northwestern University Center for Advanced Molecular Imaging, Evanston, IL (E.A.W.); and Computation Institute, University of Chicago, IL (L.L.P.).
Genetic mutations in the MYBPHL gene can cause dilated cardiomyopathy and arrhythmias. This study identified a novel MYBPHL gene mutation, linking it to heart dysfunction and conduction abnormalities in mice.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Cardiomyopathy and arrhythmias have a strong genetic basis.
- Previous genetic testing was inconclusive for a family with dilated cardiomyopathy and conduction disease.
Purpose of the Study:
- To investigate the genetic cause of inherited cardiomyopathy and arrhythmias in a family.
- To elucidate the role of the MYBPHL gene in cardiac function and conduction.
Main Methods:
- Whole-genome sequencing was performed on affected family members.
- Induced pluripotent stem cells were used for cellular modeling.
- A mouse model with Mybphl gene deletion was created and analyzed.
Main Results:
- A novel premature stop codon (R255X) in the MYBPHL gene was identified.
- Truncated MyBP-HL protein failed to integrate into myofilaments, impacting cardiac structure.
- Mybphl-deficient mice exhibited reduced ventricular function, enlarged atria, and conduction abnormalities.
Conclusions:
- MYBPHL truncations are associated with impaired ventricular function and cardiac conduction defects.
- These findings suggest MYBPHL mutations increase the risk for human arrhythmias and cardiomyopathy.
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