# Genome-Engineered Stem Cell Models to Determine Disease Mechanisms in MYBPC3 Hypertrophic Cardiomyopathy

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $163,620

## Abstract

ABSTRACT
Hypertrophic cardiomyopathy (HCM) is the most common Mendelian inherited cardiac disease and can be
complicated by heart failure, arrhythmias, and sudden death. Over 60% of genetically-defined HCM is due to
mutations in MYBPC3. Most MYBPC3 mutations cause premature protein truncations, but the specific
mechanisms by which these mutations lead to hypertrophy and arrhythmias is elusive. These mutations may
lead to loss of function (haploinsufficiency) but may also exert dominant negative effects from truncated
MYBPC3 protein. My previous work has demonstrated an increase in MYBPC3 at the transcript level and no
difference in protein abundance, countering the loss of function hypothesis. I have further shown in preliminary
data that truncated MYBPC3 proteins demonstrate a capacity for dominant negative effects since they are able
to incorporate in the cardiac sarcomere but mislocalize and negatively influence contractility. I hypothesize that
truncating mutations in MYBPC3 exert genotype-specific dominant negative effects that impair sarcomere
organization, predispose to arrhythmia, and activate hypertrophic signalling. The hypothesis will be explored
with three specific aims, which leverage both human induced pluripotent stem cells derived cardiomyocytes
(hiPSC-CMs) to investigate early consequences of MYBPC3 mutations, and mouse models to investigate late
consequences of MYBPC3 mutations. The first aim utilizes hiPSC lines that have been genome-engineered
using the CRISPR-Cas9 system to create lines that are genetically identical except for an allelic spectrum of
three specific MYBPC3 mutations. HiPSC-CM immaturity is addressed using modified cell culture substrates
and micropatterning techniques. These hiPSC-CMs will be compared for sarcomere organization, contractility,
calcium handling, and arrhythmia susceptibility. The second aim compares a heterozygous MYBPC3 knock-out
mouse model with a heterozygous MYBPC3 knock-in (truncating mutation) mouse model, which are direct
corollaries for the hiPSC-CM models in the first aim, and will be compared at 6 months for analogous in vivo
phenotypes that reflect chronic adverse remodeling. The third aim explores the hypothesis that the calcineurin-
CaMKII signaling pathway is critical in the pathogenesis of hypertrophy and arrhythmia susceptibility due to
truncating mutations in MYBPC3, as supported by my preliminary data for this pathway in human HCM. The
proposal will provide convincing evidence for the role of truncated MYBPC3 dominant negative effects as a
mechanistic upstream cause of sarcomere dysfunction, arrhyhthmias, and calcium mishandling in HCM.
Furthermore, the findings will have imminent clinical impact since truncating MYBPC3 mutations are the most
common genetic cause of HCM, and therefore results of this study have high potential for influencing future
genotype-specific therapeutic development. The proposed project and career development plan will also be an
excellent training veh...

## Key facts

- **NIH application ID:** 9984504
- **Project number:** 5K08HL130455-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ADAM S HELMS
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $163,620
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984504

## Citation

> US National Institutes of Health, RePORTER application 9984504, Genome-Engineered Stem Cell Models to Determine Disease Mechanisms in MYBPC3 Hypertrophic Cardiomyopathy (5K08HL130455-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984504. Licensed CC0.

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