Servián-Morilla, E.Cabrera-Serrano, M.Rivas-Infante, E.Carvajal, A.Lamont, P. J.Pelayo-Negro, A. L.Ravenscroft, G.Junckerstorff, R.Dyke, J. M.Fletcher, S.Adams, A. M.Mavillard, F.Fernández-García, M. A.Nieto-González, J. L.Laing, N. G.Paradas, C.2020-08-242020-08-242019-03-01Servián-Morilla E, Cabrera-Serrano M, Rivas-Infante E, Carvajal A, Lamont PJ, Pelayo-Negro AL, et al. Altered myogenesis and premature senescence underlie human TRIM32-related myopathy. Acta Neuropathol Commun. 2019 Mar 1;7(1):30.http://hdl.handle.net/10668/3168TRIM32 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.enMuscle dystrophyTRIM32E3 ubiquitin-ligaseProliferation/differentiationAutophagyMuscular dystrophiesDistrofias muscularesCell proliferationProliferación celularCell differentiationDiferenciación celularAutofagiaMedical Subject Headings::Anatomy::Cells::Cells, CulturedMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Musculoskeletal Development::Muscle DevelopmentMedical Subject Headings::Diseases::Musculoskeletal Diseases::Muscular DiseasesMedical Subject Headings::Anatomy::Cells::Stem Cells::MyoblastsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::PedigreeMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription FactorsMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Ubiquitin-Protein Ligase Complexes::Ubiquitin-Protein LigasesMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell ProliferationMedical Subject Headings::Diseases::Musculoskeletal Diseases::Muscular Diseases::Muscular Disorders, Atrophic::Muscular DystrophiesMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Autophagyresearch article30823891open access10.1186/s40478-019-0683-92051-5960PMC6396567