Abstract Body: Background: No current animal models re-capitulate MyBP-c haploinsufficiency and hypertrophic cardiomyopathy (HCM) observed in patients with heterozygous MYBPC3 truncating variants, the most common genetic cause of HCM. We recently identified a hypomorphic (partial) loss of function MYBPC3 variant that increases disease severity in HCM patients when combined with an MYBPC3 truncating variant.
Hypothesis: Additive effects from a hypomorphic loss of function MYBPC3 variant observed in human HCM will result in MyBP-c protein haploinsufficiency and HCM in a biallelic murine model.
Methods: To test MYBPC3 dose effects, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were first derived from an HCM patient with biallelic hypomorphic and complete loss of function variants in MYBPC3. We then generated Mybpc3 knock out (Mybpc3^KO) and hypomorphic knock in (Mybpc3^KI) alleles in mice. Control (Mybpc3^+/+), monoallelic, and biallelic mice and iPSC-CMs were characterized with morphometric measurements, echocardiography, mass spectroscopy, and RNA sequencing.
Results: Biallelic iPSC-CMs demonstrated haploinsufficiency not present in heterozygous models through dose reduction in MYBPC3 protein (Fig 1A). Similarly, biallelic Mybpc3^KI/KO mice had a reduction in Mybpc3 transcripts (62±3%, p<0.001) with 43±11%% reduction in MyBP-c protein (Fig 1B) and cardiac hypertrophy (10±5% increase in heart mass, p=0.002, Fig 1C).
Conclusions: Graded reduction in Mybpc3 transcripts in a biallelic mouse model results in MyBP-c haploinsufficiency similar to that observed in HCM patients. Corresponding hypertrophy establishes this approach as a clinically relevant, novel model of MYBPC3 HCM.