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

Christopher T. Pappas, Rachel M. Mayfield, Ava E. Dickerson, Lei Mi-Mi, Carol C. Gregorio

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere1011279
JournalPLoS genetics
Issue number5 May
StatePublished - May 15 2024

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


Dive into the research topics of 'Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay'. Together they form a unique fingerprint.

Cite this