TRIM32 – Autosomal Recessive Limb-Girdle Muscular Dystrophy

TRIM32 is an E3 ubiquitin ligase containing RING, B-box, coiled-coil and six NHL repeats. Biallelic pathogenic variants in TRIM32 result in autosomal recessive limb-girdle muscular dystrophy (AR-LGMD, MONDO:0015152), characterized by progressive proximal muscle weakness, variable age of onset, hyperCKemia and eventual loss of ambulation. Cardiac involvement and respiratory insufficiency are also reported across subtypes, underscoring the need for multidisciplinary care. (PMID:30919934)

Genetic analyses in a Dutch LGMD cohort identified one patient with homozygous TRIM32 mutations (A (p.Asp487Asn), segregates in Manitoba Hutterite kindreds and was found homozygous in multiple affected individuals; four additional LGMD2H patients carried novel NHL-clustered alleles including frameshift c.1560del (p.Cys521fs). These variants were absent in controls and follow an autosomal recessive inheritance pattern. (PMID:17994549)

Yeast two-hybrid assays demonstrate that c.1459G>A (p.Asp487Asn) and other NHL mutants abolish TRIM32 self-interaction and impair binding to the E2 enzyme E2N, indicating loss of E3 ligase function. A knock-in mouse model carrying the orthologous Asp489Asn mutation shows severe reduction of TRIM32 protein and recapitulates both myopathic and neurogenic features observed in Trim32 knock-outs. Satellite cell assays reveal premature senescence, impaired myogenesis and defective muscle regrowth after atrophy. Costamere integrity is disrupted in Drosophila thin mutants, orthologous to human TRIM32, with progressive myofibril breakdown. (PMID:21775502, PMID:22505452, PMID:23071324)

No convincing evidence disputes TRIM32’s role in AR-LGMD; allelic mutations in the B-box domain cause Bardet-Biedl syndrome without muscle involvement, supporting domain-specific mechanisms. (PMID:17994549)

Collectively, genetic and experimental data support a loss-of-function mechanism for TRIM32 in AR-LGMD. Biallelic NHL domain variants destabilize the protein, disrupt ubiquitination of substrates (e.g., dysbindin, NDRG2, SERCA1a), compromise satellite cell function and costamere stability, and reproduce human muscle pathology in vivo and in vitro. Further natural history studies and variant-specific functional assays may refine genotype–phenotype correlations and inform therapeutic development.

Key Take-home: Biallelic loss-of-function TRIM32 variants in the NHL domain cause AR-LGMD2H via impaired ubiquitin ligase activity, leading to muscle degeneration, with strong clinical utility for genetic diagnosis and variant interpretation.

References

• Clinical Genetics • 2019 • Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. PMID:30919934
• Human Mutation • 2008 • Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H. PMID:17994549
• Human Molecular Genetics • 2011 • 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. PMID:21775502
• The Journal of Clinical Investigation • 2012 • Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H. PMID:22505452
• Proceedings of the National Academy of Sciences of the United States of America • 2012 • Thin, a Trim32 ortholog, is essential for myofibril stability and is required for the integrity of the costamere in Drosophila. PMID:23071324

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