Rare TRIM63 variants were significantly enriched in white patients with hypertrophic cardiomyopathy compared to controls (4.4% vs 1.1%, P=0.024) and imparted loss-of-function effects.
Case-Control (n=1,392)
TRIM63 mutations are identified as a novel genetic cause of human hypertrophic cardiomyopathy, acting through impaired protein degradation.
Absolute Event Rate: 4.4% vs 1.1%
p-value: p=0.024
RATIONALE: A delicate balance between protein synthesis and degradation maintains cardiac size and function. TRIM63 encoding Muscle RING Finger 1 (MuRF1) maintains muscle protein homeostasis by tagging the sarcomere proteins with ubiquitin for subsequent degradation by the ubiquitin-proteasome system (UPS). OBJECTIVE: To determine the pathogenic role of TRIM63 in human hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Sequencing of TRIM63 gene in 302 HCM probands (250 white individuals) and 339 control subjects (262 white individuals) led to identification of 2 missense (p.A48V and p.I130M) and a deletion (p.Q247*) variants exclusively in the HCM probands. These 3 variants were absent in 751 additional control subjects screened by TaqMan assays. Likewise, rare variants were enriched in the white HCM population (11/250, 4.4% versus 3/262, 1.1%, respectively, P=0.024). Expression of the mutant TRIM63 was associated with mislocalization of TRIM63 to sarcomere Z disks, impaired auto-ubiquitination, reduced ubiquitination and UPS-mediated degradation of myosin heavy chain 6, cardiac myosin binding protein C, calcineurin (PPP3CB), and p-MTOR in adult cardiac myocytes. Induced expression of the mutant TRIM63 in the mouse heart was associated with cardiac hypertrophy, activation of the MTOR-S6K and calcineurin pathways, and expression of the hypertrophic markers, which were normalized on turning off expression of the mutant protein. CONCLUSIONS: TRIM63 mutations, identified in patients with HCM, impart loss-of-function effects on E3 ligase activity and are probably causal mutations in HCM. The findings implicate impaired protein degradation in the pathogenesis of HCM.
Chen et al. (Fri,) conducted a case-control in Hypertrophic cardiomyopathy (n=1,392). TRIM63 rare variants vs. Wild-type TRIM63 (control subjects) was evaluated on Presence of rare TRIM63 variants in the white population (p=0.024). Rare TRIM63 variants were significantly enriched in white patients with hypertrophic cardiomyopathy compared to controls (4.4% vs 1.1%, P=0.024) and imparted loss-of-function effects.