Abstract
Modifier genes contribute to the diverse clinical manifestations of hypertrophic cardiomyopathy (HCM), but are still largely unknown. Muscle ring finger (MuRF) proteins are a class of muscle-specific ubiquitin E3-ligases that appear to modulate cardiac mass and function by regulating the ubiquitin-proteasome system. In this study we screened all the three members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM patients and 307 healthy controls by targeted resequencing. Identified rare variants were confirmed by capillary Sanger sequencing. The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2%) vs. 1/307 (0.3%), p = 0.04; MuRF2 22/594 (3.7%) vs. 2/307 (0.7%); p = 0.007). Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04) and had greater maximum left ventricular wall thickness (p = 0.006) than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9%) of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.
Highlights
Hypertrophic cardiomyopathy (HCM) is defined by the presence of left ventricular hypertrophy in the absence of loading conditions sufficient to cause the observed abnormality [1]
The phenotypes of hypertrophic cardiomyopathy (HCM) patients were ascertained to determine whether rare variants of MuRF1 and MuRF2 modify the clinical expression of the disease (Tables 3 and S3)
Impairment of the ubiquitin-proteasome system (UPS) may underlie the association of rare variants in the genes encoding MuRF1 and MuRF2 with increased risk for HCM and greater severity of phenotypic expressions observed in our study
Summary
Hypertrophic cardiomyopathy (HCM) is defined by the presence of left ventricular hypertrophy in the absence of loading conditions sufficient to cause the observed abnormality [1] It is the most common monogenic cardiovascular disease, caused mainly by mutations in genes encoding sarcomere proteins [2,3,4,5]. Muscle ring finger (MuRF) proteins MuRF1, 2 and 3 (encoded by TRIM63, TRIM55 and TRIM54, respectively) comprise a subfamily of the RING-finger E3 ubiquitin ligases that are expressed in striated muscles [14,15] They can create complexes as homodimers and heterodimers, and regulate myocyte size and contractility through proteasome-dependent degradation of sarcomere proteins and transduction factors of hypertrophic signaling [16,17,18,19,20,21,22,23]. We evaluated the association between genetic variants of MuRF genes and HCM phenotype by screening all the three members of MuRF subfamily in a large HCM cohort and matched healthy controls
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