# Biological Basis of Genetic cMyBP-C Cardiomyopathies

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $692,971

## Abstract

ABSTRACT
This collaborative project integrates fundamental molecular biology, cell level biophysics, animal-level
physiology, and computer modeling to advance understanding of molecular mechanisms by which inherited
mutations in cardiac myosin binding protein C (cMyBP-C) cause disease. Some individuals who inherit mutations
in this protein are at increased risk of developing hypertrophic cardiomyopathy but clinicians know that not all
mutations lead to significant disease. Linking genotype to phenotype is particularly challenging for missense
mutations as these often cause cMyBP-C molecules with abnormal function to be expressed in a patient’s heart.
More than 1000 missense mutations have already been identified but there is rarely enough clinical information
to determine the severity and/or best treatments for a given variant. Therefore, most are still characterized as
variants of unknown significance. Further, the field’s understanding of the basic mechanisms by which missense
mutations in cMyBP-C cause disease is limited because cMyBP-C exhibits complex behaviors and it’s N-terminal
and central domains can impact contractile function in diverse ways by interacting with both myosin and actin.
While it seems likely that the mutation’s location on the molecule determines its impact on contractile function,
mechanistic analyses of the region-specific molecular underpinnings of cMyBP-C missense variants has not yet
been performed.
The large number of variants makes it impractical to create animal or cell-based models for each missense
mutation. This project advances the field by combining strategically selected biological experiments with
computer modeling to develop a data-driven pipeline that can ultimately be used to identify which missense
mutations currently classified as variants of unknown significance pose the greatest risk to patients and the best
way to treat each variant.
To address this important problem we assembled a multidisciplinary research that will integrate experimental
approaches that span temporal and spatial scales, and complementary expertise in basic mechanisms of
cMyBP-C and clinical presentation of cMyBP-C related HCM. The research plan has 3 Aims:
 1) Predict the mechanisms and severity of missense mutations in cMyBP-C that cause hypertrophic
cardiomyopathy.
 2) Test predictions of cardiac phenotype using AAV9 to express mutant cMyBP-C in mouse hearts.
 3) Use a data-driven mechanistic approach to determine the most effective treatment for cMyBP-C variants.
The plan is highly innovative and makes intelligent use of the skills and resources of four leading investigators.
The team are committed to developing shared resources and will publish their computer code as open-source
projects as well as sharing their cell and animal-level data as freely-accessible databases to accelerate future
research.

## Key facts

- **NIH application ID:** 10996620
- **Project number:** 1R01HL173989-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Kenneth S Campbell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $692,971
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996620

## Citation

> US National Institutes of Health, RePORTER application 10996620, Biological Basis of Genetic cMyBP-C Cardiomyopathies (1R01HL173989-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10996620. Licensed CC0.

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