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Developmental MYH3 Myopathy Associated with Expression of Mutant Protein and Reduced Expression Levels of Embryonic MyHC
Department of Clinical and Medical Genetics, University of Gothenburg, Sweden.
Department of Clinical and Medical Genetics, University of Gothenburg, Sweden.
Proteomic Core Facility, Sahlgrenska Academy, University of Gothenburg, Sweden.
Department of Clinical and Medical Genetics, University of Gothenburg, Sweden.
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, e0142094Article in journal (Refereed) Published
Abstract [en]


An essential role for embryonic MyHC in foetal development has been found from its association with distal arthrogryposis syndromes, a heterogeneous group of disorders characterised by congenital contractions. The latter probably result from severe myopathy during foetal development. Lack of embryonic muscle biopsy material and suitable animal models has hindered study of the pathomechanisms linking mutations in MYH3 to prenatal myopathy.


We determined the pathomechanisms of developmental myopathy caused by recurrent p.Thr178Ile MYH3 heterozygosity, using patient-derived skeletal muscle cells in culture as an experimental disease model to emulate early embryonic development. These cultured cells were processed for discrimination and quantitative analysis of mutant and wild-type MYH3 alleles and MyHC transcripts, real-time RT-qPCR, sequence analysis, immunofluorescence microscopy, immunoblot, and proteomic assessments. Involvement of the ubiquitin proteasome system was investigated in patients with p.Thr178Ile mutations in MYH3 and MYH2. We found equal overall expression of mutant and wild-type MyHC mRNAs and proteins. Compared to the controls, however, expression of embryonic MyHC transcripts and proteins was reduced whereas expression of myosin-specific E3 ubiquitin ligase (MuRF1) was increased. We also found delayed myofibrillogenesis and atrophic myotubes but structured sarcomeres.


In conclusion, this study suggests that developmental p.Thr178Ile MYH3 myopathy is associated with a combined pathomechanism of insufficient dosage of functional embryonic MyHC and production of mutant protein.

Place, publisher, year, edition, pages
Public Library Science , 2015. Vol. 10, no 11, e0142094
Keyword [en]
myosin heavy-chain, skeletal muscle, IIB-myosin, in-vivo, gene, mutations, hypertrophy, atrophy, mouse, mice
National Category
Clinical Medicine
Research subject
Medical sciences
URN: urn:nbn:se:his:diva-11762DOI: 10.1371/journal.pone.0142094ISI: 000364398700080PubMedID: 26544689OAI: diva2:883099
Swedish Research Council
Available from: 2015-12-16 Created: 2015-12-16 Last updated: 2016-01-25Bibliographically approved

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