Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Ubiquitin-Proteasome System

Background:

• Modifier genes significantly influence hypertrophic cardiomyopathy (HCM) clinical variability, but remain largely unidentified.
• Muscle RING Finger (MuRF) proteins, muscle-specific E3 ubiquitin ligases, regulate cardiac mass and function via the ubiquitin-proteasome system.

Purpose of the Study:

• To investigate the role of MuRF1, MuRF2, and MuRF3 gene variants in the pathogenesis of hypertrophic cardiomyopathy (HCM).
• To determine the association between rare MuRF variants and clinical manifestations in HCM patients.

Main Methods:

• Targeted resequencing of MuRF1, MuRF2, and MuRF3 in 594 unrelated HCM patients and 307 healthy controls.
• Confirmation of identified rare variants using capillary Sanger sequencing.
• Comparison of variant prevalence and clinical characteristics between HCM patients and controls.

Main Results:

• Rare variants in MuRF1 and MuRF2 were significantly more prevalent in HCM patients than in controls (MuRF1: 2.2% vs. 0.3%; MuRF2: 3.7% vs. 0.7%).
• HCM patients with rare MuRF1 or MuRF2 variants were younger and exhibited greater maximum left ventricular wall thickness.
• Nearly 56% of HCM patients with MuRF1/MuRF2 variants also had mutations in sarcomere protein-encoding genes.

Conclusions:

• Rare variants in MuRF1 and MuRF2 are associated with increased penetrance and more severe clinical phenotypes in HCM.
• Dysregulation of the ubiquitin-proteasome system, mediated by MuRF proteins, is implicated in the pathogenesis of HCM.
• MuRF1 and MuRF2 represent potential genetic modifiers and therapeutic targets in hypertrophic cardiomyopathy.