title: The common missense mutation D489N in TRIM32 causing limb girdle muscular dystrophy 2H leads to loss of the mutated protein in knock-in mice resulting in a Trim32-null phenotype.
abstract: Mutations in tripartite motif protein 32 (TRIM32) are responsible for several hereditary disorders that include limb girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathy (STM) and Bardet Biedl syndrome. Most LGMD2H mutations in TRIM32 are clustered in the NHL β-propeller domain at the C-terminus and are predicted to interfere with homodimerization. To get insight into TRIM32's role in the pathogenesis of LGMD2H and to create an accurate model of disease, we have generated a knock-in mouse (T32KI) carrying the c.1465G > A (p.D489N) mutation in murine Trim32 corresponding to the human LGMD2H/STM pathogenic mutation c.1459G > A (p.D487N). Our data indicate that T32KI mice have both a myopathic and a neurogenic phenotype, very similar to the one described in the Trim32-null mice that we created previously. Analysis of Trim32 gene expression in T32KI mice revealed normal mRNA levels, but a severe reduction in mutant TRIM32 (D489N) at the protein level. Our results suggest that the D489N pathogenic mutation destabilizes the protein, leading to its degradation, and results in the same mild myopathic and neurogenic phenotype as that found in Trim32-null mice. Thus, one potential mechanism of LGMD2H might be destabilization of mutated TRIM32 protein leading to a null phenotype.
authors.affiliation: Department of Neurology, Center for Duchenne Muscular Dystrophy at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Kudryashova
authors.forename: Arie
authors.initials: A
authors.lastname: Struyk
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Mokhonova
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cannon
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Spencer
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D018390:Gene Targeting; D051379:Mice; D008822:Mice, Transgenic; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D009218:Myosins / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases; D009218:Myosins