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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.).
Insights
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.
Background:
Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing.
Methods:
Whole-genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of Mybphl.
Results:
Whole-genome sequencing identified a premature stop codon, R255X, in the MYBPHL gene encoding MyBP-HL (myosin-binding protein-H like), a novel member of the myosin-binding protein family. MYBPHL was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant MYBPHL allele. Echocardiography of Mybphl heterozygous and null mouse hearts exhibited a 36% reduction in fractional shortening and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in Mybphl heterozygous and null mice. Using a reporter system, we detected robust expression of Mybphl in the atria, and in discrete puncta throughout the right ventricular wall and septum, as well. Telemetric electrocardiogram recordings in Mybphl mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice.
Conclusions:
The findings of reduced ventricular function and conduction system defects in Mybphl mice support that MYBPHL truncations may increase risk for human arrhythmias and cardiomyopathy.
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