# Dissecting the mechanism of how dominant negative MYH7 mutations lead to genetic cardiomyopathies

> **NIH VA IK2** · VA PUGET SOUND HEALTHCARE SYSTEM · 2020 · —

## Abstract

Dilated and “burnt out” hypertrophic cardiomyopathies are common genetic cardiomyopathies that lead
to heart failure. Currently over 115,000 Veterans annually receive care for heart failure from the VA Health
Care System. Despite efforts to implement guideline-directed medical therapy, the overall 5 year mortality is
~50% after diagnosis, so clearly this is a disease important to not only Veterans but also the general
population.
 Myosin heavy chain 7 (MYH7) mutations are common causes of hypertrophic and dilated
cardiomyopathies. Genetic testing for MYH7 variants have been limited by frequent identification of variants of
unknown significance and the lack of disease-modifying therapies when pathogenic variants are identified. This
proposal will identify MYH7 variants that will cause contractile dysfunction, the first step to the development of
heart failure, and study the disease pathogenesis in human induced pluripotent stem cell-derived
cardiomyocytes.
 Mutations in either the MYH7 S2 domain or the C1C2 domain of cardiac myosin binding protein C
(cMyBPC) that disrupt the normal protein-protein interaction between S2/C1C2 have recently been shown to
induce heart failure with reduced ejection fraction. This leads to the hypothesis that a subset of MYH7
mutation-induced cardiomyopathies are due to impaired interaction between these two proteins. The proposed
work uses saturation mutagenesis and high-throughput modified yeast two-hybrid assays to identify nearly all
mutations in the MYH7 S2 domain that disrupt normal protein-protein interaction with the C1C2 domain of
cMyBPC. This will assist in identifying all clinically relevant MYH7 S2 variants that are susceptible to
developing heart failure and generate a “look up” table that would enable the confident identification of patients
that could benefit from therapeutic intervention (Aim 1). Abnormally functioning mutant MYH7 protein raises the
possibility of increased myosin degradation. This is supported by recent work demonstrating an upregulation of
muscle RING-finger protein-1 (MuRF1), an E3 ligase that targets MYH7 and other sarcomeric proteins for
degradation, in human induced pluripotent stem cell-derived cardiomyocytes expressing the pathogenic MYH7
E848G variant. This leads to the hypothesis that MuRF1 upregulation in MYH7 mutation-induced
cardiomyopathies contributes to systolic dysfunction and that reducing MuRF1 levels will increase contractility.
The proposed work will use gain-of-function and loss-of-function experiments to elucidate the role of MuRF1 in
MYH7 mutation-induced cardiomyopathies (Aim 2). If successful it will determine if MuRF1 can be a novel
therapeutic target for these genetic cardiomyopathies.
 The proposed work uses several innovative techniques. It combines cutting-edge high-throughput
functional assays with mechanistic studies in genetically-edited human induced pluripotent stem cell-derived
cardiomyocytes to identify patients with MYH7 mutations that are at risk ...

## Key facts

- **NIH application ID:** 9784447
- **Project number:** 1IK2BX004642-01
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Kai-Chun Daniel Yang
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9784447

## Citation

> US National Institutes of Health, RePORTER application 9784447, Dissecting the mechanism of how dominant negative MYH7 mutations lead to genetic cardiomyopathies (1IK2BX004642-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9784447. Licensed CC0.

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