Compound mutations in HRC and MYBPC3 synergistically increase cardiac pathogenicity

ABSTRACT: Hypertrophic cardiomyopathy (HCM) and arrhythmia are two leading causes of sudden cardiac death (SCD). A 25-base pair deletion in intron 32 of cardiac myosin binding protein C (MYBPC3Δ25bp) results in cardiomyopathies in 6% of South Asians. Within this population, another compounded genetic variant of a Serine to Alanine mutation in the 96th codon of HRC (HRCS96A) is present with frequencies of 48% (heterozygous) and ~16% (homozygous), resulting in a higher incidence of sudden death in dilated cardiomyopathy (DCM). To elucidate the pathogenicity of impaired Ca2+-cycling and arrhythmias by the HRCS96A polymorphism in the setting of altered sarcomere function instrumented by the MYBPC3Δ25bp variant. Using transgenic mouse models, we studied the effects of the MYBPC3Δ25bp and the HRC mutation (murine S81A) alone and together (double variant, DV). Electrocardiogram tracing of DV mice also indicated increased stress-induced arrhythmias, such as ventricular tachycardia, after caffeine and epinephrine administration. In vitro, IonOptix experiments using freshly isolated adult cardiomyocytes revealed DV mice significantly decreased fractional shortening, Ca2+ transient amplitude, and higher number of after-contraction. When challenged with transverse aortic constriction (TAC), the DV mice also displayed more severe systolic and diastolic dysfunction as measured by echocardiography. In subsequent RNA sequencing studies, compared to the non-transgenic controls, the DV mice had significantly more dysregulated genes than the single-variant mice. A perturbagen screen followed the RNA sequencing study to predict small molecules could revert these pathological gene signatures in the DV mice. These studies highlight the increased pathogenicity of compound variants in calcium handling and sarcomeric genes, as evidenced by increased cardiac dysfunction at baseline and post-TAC and increased pathological gene dysregulation in the double variant mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE279737 | GEO | 2024/10/24

REPOSITORIES: GEO