Muscular Dystrophy-Associated and Variants Disrupt Nuclear-Cytoskeletal Connections and Myonuclear Organization

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Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder involving muscle wasting and weakness, accompanied by cardiac defects. The disease is variable in its severity and also in its genetic cause. So far, 6 genes have been linked to EDMD, most encoding proteins that form a structural network that supports the nucleus of the cell and connects it to structural elements of the cytoplasm. This network is particularly important in muscle cells, providing resistance to mechanical strain. Weakening of this network is thought to contribute to development of muscle disease in these patients. Despite rigorous screening, at least 50% of patients with EDMD have no detectable mutation in the 6 known genes. We therefore undertook screening and identified mutations in two additional genes that encode other components of the nuclear structural network, SUN1 and SUN2. Our findings add to the genetic complexity of this disease since some individuals carry mutations in more than one gene. We also show that the mutations disrupt connections between the nucleus and the structural elements of cytoplasm, leading to mis-positioning and clustering of nuclei in muscle cells. This nuclear mis-positioning is likely to be another factor contributing to pathogenesis of EDMD.

Vyšlo v časopise: Muscular Dystrophy-Associated and Variants Disrupt Nuclear-Cytoskeletal Connections and Myonuclear Organization. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004605
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004605

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