부산대학교 도서관

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. Author summary: Dilated cardiomyopathy is a common type of heart disease characterized by an enlarged heart that does not contract properly. Dilated cardiomyopathy results from a variety of causes including the presence of an inherited gene mutation. Mutations in the Leiomodin 2 (LMOD2) gene result in a severe form of early-onset dilated cardiomyopathy that, without intervention, leads to death within weeks of birth. The majority of LMOD2 mutations discovered to date are predicted to result in the production of a truncated protein. In all cases thus far analyzed, little to no protein is made. Here we show that a cellular quality control mechanism, referred to as nonsense mediated mRNA decay, is activated to detect and destroy the instructions for making mutant LMOD2 protein, resulting in its loss. Since it was previously shown that at least one mutant LMOD2 protein is functional, we generated a treatment that blocks activation of the quality control mechanism specifically for mutant LMOD2. This treatment results in synthesis of the mutant protein and thus, could have therapeutic potential. [ABSTRACT FROM AUTHOR]