# Myofilament proteins in cardiomyopathy and arrhythmias

> **NIH NIH K99** · NORTHWESTERN UNIVERSITY · 2020 · $97,783

## Abstract

PROJECT SUMMARY
The cardiomyocyte contractile apparatus is central to heart function. Mutations in the genes encoding
sarcomere proteins like myosin heavy chain and myosin binding protein-C cause inherited forms of
cardiomyopathy and an increased risk for cardiac arrhythmias. However, the mechanisms by which sarcomere
protein mutations lead to arrhythmias remains largely unknown. We identified a novel component of the
myofilament, myosin binding protein H-like (MyBP-HL). Myosin binding protein H was originally discovered
along with myosin binding protein C. We found that MyBP-H is encoded by two distinct genes, MYBPH which
specifies H-protein in skeletal muscle, and MYBPHL, which generates the H-protein of the heart. Moreover,
we discovered that MYBPHL is highly enriched in the atria and expressed throughout the ventricle in a pattern
consistent with ventricular conduction system cells. We identified a premature stop variant in MYBPHL
(R255X) in a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. Deletion of Mybphl in
mice recapitulates this human phenotype, including atrial and ventricular arrhythmias and dilated
cardiomyopathy. Despite low-level expression of MYBPHL in the left ventricle, heterozygous mutations of
MYBPHL in mice and humans leads to left ventricular dysfunction. These observations suggest that MyBP-HL
regulates myofilament content in the cardiac conduction system, an understudied area with regard to
myofilament content and regulation. We hypothesize that MyBP-HL regulates sarcomere size and contractility
and contributes to the function and morphology of ventricular conduction cells, and that loss of MyBP-HL leads
to structural changes of these cells which, in turn, promotes arrhythmias and left ventricular dysfunction. We
propose to study Mybphl in ventricular conduction cells by crossing the Mybphl null mouse with a conduction
system reporter mouse and by creating a conditional Mybphl null mouse line for deletion of Mybphl in the adult
heart and in the ventricular conduction system specifically. Dr. David Barefield, the PI of this project, has a
strong background studying myofilament proteins and mouse models of cardiomyopathy. The training
proposed in this study will allow Dr. Barefield to study mouse models of arrhythmia in order to establish the role
of MYBPHL in regulating the ventricular conduction system. This will be done by collaborating with experts in
techniques for studying whole-animal, whole-heart, and cellular electrophysiology. The candidate is taking the
steps to become an independent academic investigator with his own laboratory at a university or medical
research center in the United States. The exceptional environment and commitment to this research at
Northwestern University, in addition to the expert team of co-mentors provides an outstanding environment to
achieve the goals set out in this proposal.

## Key facts

- **NIH application ID:** 9839418
- **Project number:** 5K99HL141698-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** David Y Barefield
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $97,783
- **Award type:** 5
- **Project period:** 2018-12-15 → 2020-08-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839418

## Citation

> US National Institutes of Health, RePORTER application 9839418, Myofilament proteins in cardiomyopathy and arrhythmias (5K99HL141698-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9839418. Licensed CC0.

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