1. Altered myogenesis and premature senescence underlie human TRIM32-related myopathy
- Author
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Emilia Servián-Morilla, A. L. Pelayo-Negro, Macarena Cabrera-Serrano, Fabiola Mavillard, Nigel G. Laing, Abbie M. Adams, Gianina Ravenscroft, Alejandra Carvajal, M. A. Fernández-García, Sue Fletcher, Jose Luis Nieto-Gonzalez, Carmen Paradas, Reimar Junckerstorff, E. Rivas-Infante, J. M. Dyke, Phillipa J. Lamont, Instituto de Biomedicina de Sevilla (IBIS), [Servian-Morilla,E, Cabrera-Serrano,M, Mavillard,F, Paradas,C] Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain. [Servian-Morilla,E, Nieto-González,JL, Paradas,C] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Cabrera-Serrano,M, Rivas-Infante,E, Lamont,PJ, Ravenscroft,G, Laing,NG] Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, Australia. [Rivas-Infante,E] Department of Neuropathology, Hospital U. Virgen del Rocío/ Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain. [Carvajal,A] Neuromuscular Unit, Hospital Virgen de las Nieves, Granada, Spain. [Pelayo-Negro,AL] Neurology Department, University Hospital Marqués de Valdecilla (IDIVAL), Santander, Cantabria, Spain. [Junckerstorff,R, Dyke,JM] PathWest Laboratory Medicine WA, Section of Neuropathology, Royal Perth Hospital, Perth, WA, Australia. [Fletcher,S, Adams,AM] Centre for Comparative Genomics, Murdoch University, Perth, Australia. [Fletcher,S, Adams,AM] Perron Institute for Neurological and Translational Science, University of Western Australia, Nedlands, Australia. [Fernández-García,MA] Neurology Department, Health in Code S.L., A Coruña, Spain. [Nieto-González,JL] Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain., Supported in part by grants from the Health Institute Carlos III and FEDER a way to achieve Europe (PI16–01843 to CP, JR15/00042 to MC-S), the Fundación Progreso y Salud, Junta de Andalucía (PI-0085-2016 to JLN-G), and Australian National Health and Medical Research Council (NHMRC) Fellowships (APP1122952 and APP1117510 to GR and NGL)., Instituto de Salud Carlos III, European Commission, Junta de Andalucía, and National Health and Medical Research Council (Australia)
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0301 basic medicine ,Male ,Muscular dystrophies ,Diseases::Musculoskeletal Diseases::Muscular Diseases [Medical Subject Headings] ,Diseases::Musculoskeletal Diseases::Muscular Diseases::Muscular Disorders, Atrophic::Muscular Dystrophies [Medical Subject Headings] ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Pedigree [Medical Subject Headings] ,Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Musculoskeletal Development::Muscle Development [Medical Subject Headings] ,Muscle Development ,Anatomy::Cells::Stem Cells::Myoblasts [Medical Subject Headings] ,lcsh:RC346-429 ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Myoblasts ,Tripartite Motif Proteins ,0302 clinical medicine ,E3 ubiquitin -ligase ,Proliferation/differentiation ,Cell differentiation ,Myocyte ,Missense mutation ,Diferenciación celular ,Muscular dystrophy ,Cell proliferation ,Cells, Cultured ,Cellular Senescence ,Myogenesis ,Middle Aged ,E3 ubiquitin-ligase ,3. Good health ,Pedigree ,Female ,medicine.symptom ,Senescence ,Adult ,Proliferación celular ,Ubiquitin-Protein Ligases ,Autofagia ,Check Tags::Male [Medical Subject Headings] ,Biology ,Distrofias musculares ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors [Medical Subject Headings] ,Pathology and Forensic Medicine ,Frameshift mutation ,Muscle dystrophy ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Atrophy ,Muscular Diseases ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Ubiquitin-Protein Ligase Complexes::Ubiquitin-Protein Ligases [Medical Subject Headings] ,medicine ,Autophagy ,Humans ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings] ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Autophagy [Medical Subject Headings] ,Myopathy ,lcsh:Neurology. Diseases of the nervous system ,TRIM32 ,Aged ,Research ,medicine.disease ,030104 developmental biology ,Check Tags::Female [Medical Subject Headings] ,Anatomy::Cells::Cells, Cultured [Medical Subject Headings] ,Cancer research ,Neurology (clinical) ,030217 neurology & neurosurgery ,Transcription Factors - 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., Supported in part by grants from the Health Institute Carlos III and FEDER a way to achieve Europe (PI16–01843 to CP, JR15/00042 to MC-S), the Fundación Progreso y Salud, Junta de Andalucía (PI-0085-2016 to JLN-G), and Australian National Health and Medical Research Council (NHMRC) Fellowships (APP1122952 and APP1117510 to GR and NGL).
- Published
- 2019