title: Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy.
abstract: BACKGROUND
  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).
  
  
  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.
authors: Institute of Molecular Medicine, University of Texas Health Sciences Center, Texas Heart Institute at St Luke's Episcopal Hospital, 6770 Bertner St, Suite C900A, Houston, TX 77030, USA.
authors: Suet Nee
authors: SN
authors: Chen
authors: Grazyna
authors: G
authors: Czernuszewicz
authors: Yanli
authors: Y
authors: Tan
authors: Raffaella
authors: R
authors: Lombardi
authors: Jianping
authors: J
authors: Jin
authors: James T
authors: JT
authors: Willerson
authors: Ali J
authors: AJ
authors: Marian
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012518:Sarcomeres / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C440908:TRIM63 protein, human; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin