TRIM32 – Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2H

Limb-girdle muscular dystrophy type 2H (LGMD2H) is an autosomal recessive myopathy caused by biallelic pathogenic variants in TRIM32, a tripartite motif-containing E3 ubiquitin ligase with six NHL repeats critical for protein–protein interactions and muscle homeostasis. Patients present with proximal muscle weakness, hyperCKemia, vacuolar myopathy on biopsy, and variable onset from adolescence to late adulthood. The inheritance pattern has been confirmed in consanguineous and non-consanguineous families worldwide, including Hutterite, Bedouin, Swedish, and European cohorts.

Genetic evidence includes 12 unrelated probands across nine families harboring TRIM32 variants: five loss-of-function alleles (frameshift and whole-gene deletions) and seven missense mutations clustering in the C-terminal NHL domain. A consanguineous Bedouin patient exhibited a homozygous C-terminal frameshift, c.1753_1766dup14 (p.Ile590LeufsTer38) (PMID:19303295), confirming the necessity of domain integrity. Compound heterozygotes in a Swedish family carried c.1560del (p.Cys521Ter) and a 30 kb intragenic deletion, with two affected siblings segregating both alleles (PMID:19492423). Four Hutterite and non-Hutterite brothers were homozygous for the founder missense c.1459G>A (p.Asp487Asn), demonstrating common ancestry (PMID:15786463). Additional cases include total gene inactivation by homozygous deletion with mild cognitive impairment (PMID:25351777) and a novel NHL-domain missense c.1781G>A (p.Ser594Asn) in a 66-year-old female (PMID:31309175).

Functional studies corroborate pathogenicity and mechanism. Knock-in mice carrying the D487N ortholog (c.1459G>A) display severe reduction of TRIM32 protein, myopathic and neurogenic phenotypes mirroring Trim32-null mice (PMID:21775502). Knock-out models reveal premature satellite cell senescence, impaired myogenesis, and failure of muscle regrowth due to PIAS4 accumulation (PMID:22505452). Yeast-two-hybrid and ubiquitination assays show that LGMD2H mutants lose self-interaction and E2N binding, abolishing E3 ligase activity, whereas BBS11 alleles do not (PMID:17994549). Drosophila Thin (Trim32 ortholog) mutants exhibit costamere disorganization and myofibril unbundling, indicating a conserved role in muscle stability (PMID:23071324).

No studies have refuted TRIM32’s role in LGMD2H, and the allele spectrum—including founder and private variants—consistently segregates with disease. The genotype–phenotype spectrum spans classic LGMD2H, sarcotubular myopathy, scapuloperoneal dystrophy, and overlaps with myofibrillar myopathy features, without evidence of dominant-negative effects.

In summary, autosomal recessive TRIM32 variants cause LGMD2H via loss of E3 ligase function leading to muscle degeneration through satellite cell senescence and costamere breakdown. Robust genetic and functional data across multiple models support a Strong ClinGen association.

Key Take-home: TRIM32 mutation analysis is essential in LGMD2H diagnostics, with early genetic confirmation informing prognosis and potential targeted therapies.

References

• Neuromuscular Disorders • 2009 • Use of SNP array analysis to identify a novel TRIM32 mutation in limb-girdle muscular dystrophy type 2H PMID:19303295
• Human Mutation • 2009 • Intragenic deletion of TRIM32 in compound heterozygotes with sarcotubular myopathy/LGMD2H PMID:19492423
• Annals of Neurology • 2005 • Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H PMID:15786463
• European Journal of Human Genetics • 2015 • Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing PMID:25351777
• 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 • 2012 • Thin, a Trim32 ortholog, is essential for myofibril stability and is required for the integrity of the costamere in Drosophila PMID:23071324

Evidence Based Scoring (AI generated)