# Functional consequences of FHC mutations in cardiac MyBPC

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $598,429

## Abstract

The long-range goal of this proposal is to define the mechanisms by which mutations in cardiac myosin binding
protein C (MyBPC) cause hypertrophic cardiomyopathy (HCM), a disease that affects up to 1 in 200 individuals,
and is the leading cause of sudden death in young adults. Nearly 60% of HCM cases are due to familial
inheritance (FHC) of an autosomal dominant disorder caused by mutations in sarcomeric proteins. Mutations in
MyBPC are among the most common causes of FHC accounting for half of all known cases. Because MyBPC
is a critical modulator of actomyosin interactions, the initial functional deficit caused by mutations in MyBPC is
expected to manifest as a defect in the regulation of cardiac muscle contraction at the myofilament level.
Whereas 60% of MyBPC truncation mutations are expected to cause haploinsufficiency, the remaining 40% of
MyBPC mutations are missense mutations, which are expected to produce full-length MyBPC. A large number
of these missense mutations are located in the central domains of MyBPC (i.e., C3-C7), which have no specific
known function, and thus it is unclear how FHC mutations located in this region of MyBPC cause disease. Our
limited understanding of these critical mechanisms severely limits options for therapeutic intervention for FHC
patients. Our preliminary data provide novel evidence that addresses our gap in knowledge and have identified
two important regulatory regions within the C4 and C5 domains of MyBPC that modulate cardiac muscle
contractile function. Based on these novel observations we have devised an experimental plan that is designed
to elucidate molecular mechanisms by which these key regions contribute to regulation of contractile function
and how FHC mutations alter this regulation. We have devised a multidisciplinary approach that spans from
computational modeling of atomic interactions to whole animal physiology which will accomplished in three
principal aims designed to: 1) Establish the functional effects of central domain MyBPC FHC mutations on the
magnitude and rate of force in cardiac fibers isolated from mouse hearts expressing HCM causing mutations,
and utilize molecular dynamic simulations to elucidate the molecular mechanisms of altered function. 2) Define
how MyBPC mutations alter actin and myosin binding properties and rotational dynamics using TPA and FRET
based sensors, and 3) Determine the in vivo functional consequences of MyBPC FHC mutations in MyBPC by
assessing ventricular contractile and hemodynamic function, and test the efficacy of a MyBPC-specific AAV9
gene-transfer rescue that normalizes contractile function. Parallel studies will utilize FHC patient-specific induced
pluripotent stem cell cardiomyocytes (iPSC-CM) to determine how these mutations cause disease in humans. It
is expected that results from these integrative studies will provide novel insights of the underlying mechanisms
by which mutations in MyBPC cause disease and will aid in the development of novel th...

## Key facts

- **NIH application ID:** 9973440
- **Project number:** 2R01HL114770-06
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Julian Stelzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $598,429
- **Award type:** 2
- **Project period:** 2013-02-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973440

## Citation

> US National Institutes of Health, RePORTER application 9973440, Functional consequences of FHC mutations in cardiac MyBPC (2R01HL114770-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973440. Licensed CC0.

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