Abstract
Mutations in the gene encoding emerin (EMD) cause Emery–Dreifuss muscular dystrophy (EDMD1), an inherited disorder characterized by progressive skeletal muscle wasting, irregular heart rhythms and contractures of major tendons. The skeletal muscle defects seen in EDMD are caused by failure of muscle stem cells to differentiate and regenerate the damaged muscle. However, the underlying mechanisms remain poorly understood. Most EDMD1 patients harbor nonsense mutations and have no detectable emerin protein. There are three EDMD-causing emerin mutants (S54F, Q133H, and Δ95–99) that localize correctly to the nuclear envelope and are expressed at wildtype levels. We hypothesized these emerin mutants would share in the disruption of key molecular pathways involved in myogenic differentiation. We generated myogenic progenitors expressing wildtype emerin and each EDMD1-causing emerin mutation (S54F, Q133H, Δ95–99) in an emerin-null (EMD−/y) background. S54F, Q133H, and Δ95–99 failed to rescue EMD−/y myogenic differentiation, while wildtype emerin efficiently rescued differentiation. RNA sequencing was done to identify pathways and networks important for emerin regulation of myogenic differentiation. This analysis significantly reduced the number of pathways implicated in EDMD1 muscle pathogenesis.
Highlights
X-linked Emery–Dreifuss muscular dystrophy (EDMD1) is an inherited disorder caused by mutations in EMD, which encodes emerin
Western blotting with antibodies against emerin confirmed successful expression of each of the emerin proteins; γ-tubulin was used as loading control (Figure 1A,B)
After 24 h, more than 90% of wildtype progenitors withdrew from the cell cycle, whereas 15.4% of EMD−/y myogenic progenitors were still active in the cell cycle (p < 0.02, Figure 1C). +EMD myogenic progenitors displayed a trend towards rescue
Summary
X-linked Emery–Dreifuss muscular dystrophy (EDMD1) is an inherited disorder caused by mutations in EMD, which encodes emerin. A few missense mutations and in-frame deletions in EMD produce detectable emerin protein [7,10,11,12]. There are four disease-causing EMD mutations within this region that result in normal emerin protein expression and localization; these are S54F, ∆95–99, Q133H, and P183H [10,23,24,25,26]. The structural consequences of these mutated forms are not yet known. It is possible these mutant proteins may either modify the 3D structure and conformational plasticity of the protein or disrupt specific emerin modification events, or
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