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Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
E Servián-Morilla1,2, M Cabrera-Serrano1,2,3, E Rivas-Infante3,4
1Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Abstract:
TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.
Insights
Mutations in the TRIM32 gene, a ubiquitin ligase, cause muscle dystrophy by affecting muscle regrowth and satellite cell function. TRIM32 protein reduction is observed across various mutations, leading to muscle weakness and senescence.
Area of Science:
- Genetics
- Molecular Biology
- Neuromuscular Disorders
Background:
- Tripartite motif-containing protein 32 (TRIM32) is an E3 ubiquitin ligase with distinct functional domains (RING, B-box, coiled-coil, NHL).
- Mutations in NHL and coiled-coil domains cause limb-girdle muscular dystrophy (LGMD2H/STM), while B-box mutations are linked to Bardet-Biedl syndrome type 11 (BBS11).
- Previous studies in mice (T32KO, T32KI) indicated TRIM32's role in muscle regeneration and satellite cell senescence.
Purpose of the Study:
- To phenotypically describe and functionally characterize TRIM32 mutations in the RING, coiled-coil, and NHL domains.
- To investigate the impact of TRIM32 mutations on muscle dystrophy development and cellular processes.
- To explore the relationship between TRIM32 mutations and overlapping symptoms of muscular dystrophy and Bardet-Biedl syndrome.
Main Methods:
- Analysis of TRIM32 protein levels in patient muscle biopsies.
- Clinical phenotyping of affected individuals, including muscle weakness assessment and muscle MRI.
- Functional characterization of patient-derived primary myoblast cultures, assessing proliferation, differentiation, satellite cell pool, senescence, and autophagy.
Main Results:
- Reduced TRIM32 protein levels were consistently observed in all patient muscles, irrespective of mutation type or domain.
- Patients exhibited variable phenotypes, predominantly proximal muscle weakness, with two cases showing features of both muscular dystrophy and Bardet-Biedl syndrome.
- Myoblast cultures displayed reduced proliferation and differentiation, a diminished satellite cell pool, accelerated muscle senescence, and activated autophagy.
Conclusions:
- TRIM32 mutations, affecting various domains, lead to muscle dystrophy characterized by reduced protein levels and impaired muscle cell functions.
- The study highlights the critical role of TRIM32 in muscle homeostasis and regeneration.
- TRIM32 dysfunction can result in overlapping phenotypes, suggesting a broader role in cellular processes beyond muscle tissue.
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