Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.

Autor:	Pappas CT; Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona, United States of America., Mayfield RM; Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona, United States of America., Dickerson AE; Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona, United States of America., Mi-Mi L; Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona, United States of America., Gregorio CC; Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona, United States of America.; Department of Medicine and Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, United States of America.
Jazyk:	angličtina
Zdroj:	PLoS genetics [PLoS Genet] 2024 May 15; Vol. 20 (5), pp. e1011279. Date of Electronic Publication: 2024 May 15 (Print Publication: 2024).
DOI:	10.1371/journal.pgen.1011279
Abstrakt:	The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations in all three family members (LMOD1-3) result in human myopathies. Mutations in the cardiac predominant isoform, LMOD2 lead to severe neonatal dilated cardiomyopathy. Most of the disease-causing mutations in the LMOD gene family are nonsense, or frameshift, mutations predicted to result in expression of truncated proteins. However, in nearly all cases of disease, little to no LMOD protein is expressed. We show here that nonsense-mediated mRNA decay, a cellular mechanism which eliminates mRNAs with premature termination codons, underlies loss of mutant protein from two independent LMOD2 disease-causing mutations. Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression. Our investigation lays the initial groundwork for potential therapeutic intervention in LMOD-linked myopathies. Competing Interests: The authors have declared that no competing interests exist. (Copyright: © 2024 Pappas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze:	MEDLINE
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