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

Elena Kudryashova, Arie Struyk, Ekaterina Mokhonova, Stephen C. Cannon, Melissa J. Spencer

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numberddr311
Pages (from-to)3925-3932
Number of pages8
JournalHuman Molecular Genetics
Volume20
Issue number20
DOIs
StatePublished - Oct 2011

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Missense Mutation
Phenotype
Mutation
Proteins
Bardet-Biedl Syndrome
Mutant Proteins
Limb-girdle muscular dystrophy type 2H
Tripartite Motif Proteins
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

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. / Kudryashova, Elena; Struyk, Arie; Mokhonova, Ekaterina; Cannon, Stephen C.; Spencer, Melissa J.

In: Human Molecular Genetics, Vol. 20, No. 20, ddr311, 10.2011, p. 3925-3932.

Research output: Contribution to journalArticle

Kudryashova, Elena ; Struyk, Arie ; Mokhonova, Ekaterina ; Cannon, Stephen C. ; Spencer, Melissa J. / 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. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 20. pp. 3925-3932.
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