Abstract
Embryonic myosin heavy chain (MyHC), encoded by MYH3, is expressed during fetal development and its expression declines rapidly after birth. The essential role of embryonic MyHC for fetal development has been highlighted by the identification of dominant MYH3 mutations associated with distal arthrogryposis (DA) syndromes. DA is a clinically and genetically heterogeneous group of disorders characterized by flexion of the joints with congenital contractions. It has been hypothesized that the congenital contractions result from reduced fetal movement and severe myopathy during a period of fetal development. Due to lack of muscle biopsy from embryos and suitable animal models, it is not yet established how MYH3 mutations cause DA. Here we address the pathogenesis of developmental myopathy caused by heterozygocity for the Thr178Ile MYH3 mutation, using cultured myotubes from a DA patient as an experimental disease model. Both mutant and wild-type alleles were expressed equally at the mRNA level. An increased expression level of both embryonic and fetal MyHCs in cultured myotubes from the patient compared to healthy controls was observed. Cultured myotubes from patient showed delayed myofibrylogenesis and reduction of cell diameters. The results suggest that developmental myopathy caused by Thr178Ile MYH3 mutation is associated with expression of mutant isoform and abnormal muscle development. Consequently, the expression of mutated embryonic MyHC may cause structural and/or functional abnormalities leading to dysfunctions during fetal development.
Published Version
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