MYBPH acts as modifier of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) patients

Abstract

Left ventricular hypertrophy is a risk factor for cardiovascular morbidity and mortality. Hypertrophic cardiomyopathy (HCM) is considered a model disease to study causal molecular factors underlying isolated cardiac hypertrophy. However, HCM manifests with various clinical symptoms, even in families bearing the same genetic defects, suggesting that additional factors contribute to hypertrophy. The gene encoding the cardiac myosin binding protein C (cMYBPC) is one of the most frequently implicated genes in HCM. Recently another myosin binding protein, myosin binding protein H (MYBPH) was shown to function in concert with cMYBPC in regulating cardiomyocyte contraction. Given the similarity in sequence, structure and the critical role MYBPH plays in sarcomere contraction, we proposed that MYBPH may be involved in HCM pathogenesis. Family-based genetic association analysis was employed to investigate the contribution of MYBPH in modifying hypertrophy. Seven single nucleotide polymorphisms and haplotypes in MYBPH were investigated for hypertrophy modifying effects in 388 individuals (27 families), in which three unique South African HCM-causing founder mutations (p.R403W and pA797T in β-myosin heavy chain gene (MYH7) and p.R92W in the cardiac troponin T gene (TNNT2)) segregate. We observed a significant association between rs2250509 and hypertrophy traits in the p.A797T MYH7 mutation group. Additionally, haplotype GGTACTT significantly affected hypertrophy within the same mutation group. MYBPH was for the first time assessed as a candidate hypertrophy modifying gene. We identified a novel association between MYBPH and hypertrophy traits in HCM patients carrying the p.A797T MYH7 mutation, suggesting that variation in MYBPH can modulate the severity of hypertrophy in HCM.

Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation

“…Relative studies had confirmed that the ACE-1 or ACE-2 mutation was associated with the severity of LV hypertrophy in HCM 42,43 . In addition, other genes such as myosin binding protein H have been investigated as modifiers of the hypertrophic variability in HCM 44 . Furthermore, complex genetic or a complex hierarchy of genetic, epigenetic, and environmental factors (such as demographic factors including age, sex, and body size, hypertension or obesity) might be involved in determining the phenotype 40 .…”

Thick Filament Protein Network, Functions, and Disease Association

“…Interestingly, the expression levels of MyBP-H are increased in the gracilis or vastus lateralis skeletal muscles of patients with amyotrophic lateral sclerosis (ALS), however the physiological significance of these observations are unknown (109). Recently, linkage disequilibrium analysis of MYH7 mutations associated with HCM and single nucleotide polymorphisms (SNP) in MYBPH described an association between increased left ventricular wall thickness in patients carrying the MYH7 A797T mutation and the MYBPH SNP rs2250509 (396). However, the exact mechanism of how the MYBPH SNP rs2250509 exacerbates left ventricular wall thickness in patients containing the MYH7 A797T mutation is currently unknown.…”

Exploring genetic modifiers of Gaucher disease: The next horizon

“…Since myosin binding protein C, the protein encoded by MYBPC3 , functions with myosin binding protein H (encoded by MYBPH ) to regulate cardiomyocyte contraction (Mouton, Loos, Moolman‐Smook, & Kinnear, ), the effect of MYBPH on disease severity was subsequently investigated. A MYBPH isoform was found to increase the thickness of heart walls in individuals with specific MYBPC3 mutations, and thus accentuate the disease manifestations (Mouton et al., ).…”