Edmd-causing emerin mutant myogenic progenitors exhibit impaired differentiation using similar mechanisms

Ashvin Iyer, James M. Holaska

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 ∆95–99) 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, ∆95–99) in an emerin-null (EMD−/y ) background. S54F, Q133H, and ∆95–99 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.

Original languageEnglish (US)
Article number1463
Pages (from-to)1-24
Number of pages24
JournalCells
Volume9
Issue number6
DOIs
StatePublished - Jun 2020

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

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