title: Limb-girdle muscular dystrophy 2H and the role of TRIM32.
abstract: Limb-girdle muscular dystrophy (LGMD) 2H is a slowly progressive condition characterized by proximal weakness, atrophy, and mildly to moderately raised levels of creatine kinase. Facial weakness, scapular winging, hypertrophied calves, and Achilles tendon contractions are not uncommon and the age of onset ranges between the first and fourth decade. LGMD2H was originally described in the Hutterite population that resides in central Canada and the Dakotas of the USA. LGMD2H was mapped to a specific mutation in the TRIM32 gene and it has subsequently been shown that the same mutation also results in the "sarcotubular myopathy" syndrome, which was described histopathologically. TRIM32 appears to be an E3 ubiquitin ligase, containing the tripartite motif common to this family of proteins (RING finger, B-box, coiled-coil). A few substrates have been identified, including actin and dysbindin. Recent studies have identified additional mutations in the C-terminal region of TRIM32 that result in a dystrophic myopathy. Although TRIM32 appears to be expressed ubiquitously, it is still not clear why certain mutations of TRIM32 would result in a phenotype relatively restricted to skeletal muscle. A mutation in the B-box region of TRIM32 has also been shown to result in a more pleiotropic disorder, Bardet-Biedl Syndrome (BBS11). This disorder is associated with obesity, retinopathy, diabetes, polydactyly, renal abnormalities, learning disability, and hypogenitalism. It is likely that C-terminal mutations in TRIM32 affect the ability of muscle proteins to be degraded by the ubiquitin-proteasome pathway.
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Perry B
authors.initials: PB
authors.lastname: Shieh
authors.forename: Elena
authors.initials: E
authors.lastname: Kudryashova
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Spencer
mesh_terms: D006801:Humans; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases