# Pathogenic mechanisms of myosin binding protein C missense variants within hypertrophic cardiomyopathy > **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $167,400 ## Abstract PROJECT SUMMARY/ABSTRACT Hypertrophic cardiomyopathy (HCM) is a common genetic disease, affecting ~ 1:500 people, with substantial clinical burden including heart failure, arrhythmia and sudden cardiac death. The most commonly affected protein is myosin binding protein C3 (MYBPC3). Defining a MYBPC3 variant as pathogenic enables clinical prognostication and genetic screening in at-risk relatives. Truncating variants of MYBPC3 cause a premature stop codon resulting in loss of function. However, missense variants in MYBPC3, often classified as variants of uncertain significance, are difficult to interpret as proteins may tolerate the substitution of one amino acid for another. Prior cellular and structural data suggest that pathogenic missense variants may lead to HCM via two distinct mechanisms. Some pathogenic missense variants normally incorporate into myofibrils and Dr. Thompson hypothesizes that these variants lead to HCM via inhibition of protein binding. To evaluate this hypothesis, in aim 1, Dr. Thompson will study alterations in protein binding caused by pathogenic missense variants using affinity mass spectrometry. Further, she will characterize a patient-derived cellular model and a knock-in mouse model of the most common pathogenic missense variant predicted to work via this mechanism, R502W, which accounts for 2.4% of HCM cases. These models will evaluate if HCM phenotypes can be reversed by expression of wild-type MYBPC3, suggesting a similar targeted therapeutic approach can be utilized for this common missense variant and truncating variants. Other pathogenic missense variants are rapidly cleared from the cell, similar to truncating variants, and Dr. Thompson hypothesizes that these variants lead to HCM via thermodynamic instability. Supporting this hypothesis, her prior computational work demonstrated that patients with HCM and a MYBPC3 VUS computationally predicted to cause subdomain misfolding exhibited higher rates of adverse clinical outcomes, similar to patients with HCM and known MYBPC3 pathogenic variant. In aim 2, she will evaluate if a step-wise experimental approach, which characterizes variants first in a high-throughput manner within individual subdomains and then within cardiomyocytes using full-length MYBPC3, will enable accelerated identification of variants which cause protein misfolding. Taken together, this work should provide novel biologic insight into the pathogenic mechanism(s) of MYBPC3 missense variants, enable improved clinical prognostication for patients with HCM and at-risk relatives, and inform personalized targeted therapeutic approaches to treat HCM. This proposal is distinct from Dr. Thompson’s prior experience in chemical biology and will provide her with valuable training in disease models of cardiomyopathy, cardiac physiology, and advanced experimental genetics. This work, her mentorship team, and the training activities described will facilitate Dr. Thompson’s development toward her ultimate goa... ## Key facts - **NIH application ID:** 10896913 - **Project number:** 5K08HL163328-03 - **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR - **Principal Investigator:** Andrea Dooley Thompson - **Activity code:** K08 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $167,400 - **Award type:** 5 - **Project period:** 2022-07-01 → 2027-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10896913 ## Citation > US National Institutes of Health, RePORTER application 10896913, Pathogenic mechanisms of myosin binding protein C missense variants within hypertrophic cardiomyopathy (5K08HL163328-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10896913. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*