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Dissertation/Thesis Abstract

The Use of Emerin-Null and EDMD-Causing Emerin Mutant Myogenic Progenitors to Elucidate the EDMD Mechanism
by Iyer, Ashvin, Ph.D., University of the Sciences in Philadelphia, 2020, 216; 27998882
Abstract (Summary)

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 background. S54F, Q133H, and Δ95-99 failed to rescue emerin-null myogenic differentiation, while wildtype emerin efficiently rescued differentiation. Each of these mutants disrupts binding to HDAC3. Thus, we tested another emerin mutant, M179, that specifically blocks binding to HDAC3. M179 also failed to rescue emerin-null myogenic differentiation. Collectively, these studies implicate the functional interaction of emerin with HDAC3 in the EDMD disease mechanism. 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.

Indexing (document details)
Advisor: Suryanarayanan, Asha, Holaska, James
Commitee: Harvison, Peter, Klase, Zachary, Janetopoulos, Christopher
School: University of the Sciences in Philadelphia
Department: Pharmacology & Toxicology
School Location: United States -- Pennsylvania
Source: DAI-B 81/12(E), Dissertation Abstracts International
Subjects: Biology
Keywords: Emerin, Myogenic differentiation, Nuclear envelope
Publication Number: 27998882
ISBN: 9798635294512
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