Key result
The LMNA missense variant c.936 G>C (p. Q312H) disrupted a normal splicing site, leading to nonsense-mediated mRNA decay with a 90% reduction in LMNA cDNA and >50% reduction in lamin A and C.
Why the study?
Nonsense-mediated mRNA decay induced by nonstop codon mutations is rare, prompting investigation of the effect of an LMNA missense mutation identified in 2 families affected by cardiac laminopathy.
Observational
LMNA missense mutation may induce NMD in familial laminopathy; leaves open generalizability and clinical utility pending larger studies.
Background: LMNA is a known causative gene of dilated cardiomyopathy and familial conduction disturbance. Nonsense-mediated mRNA decay, normally caused by nonsense mutations, is a safeguard process to protect cells from deleterious effects of inappropriate proteins from mutated genes. Nonsense-mediated mRNA decay induced by nonstop codon mutations is rare. We investigated the effect of an LMNA missense mutation identified in 2 families affected by cardiac laminopathy. Methods: Genomic DNA and total RNA were isolated from patients’ peripheral blood lymphocytes or cardiac tissue. LMNA -coding exons were screened by direct sequencing. Complementary DNAs were generated by a reverse transcription-polymerase chain reaction from total RNA. Quantitative polymerase chain reaction was performed to quantify the LMNA complementary DNA amount by using specific primers for lamins A and C. A minigene splicing reporter experiment was performed to assess the effect of detected variants on RNA splicing. The protein expressions of both isoforms were analyzed by Western blotting. Results: We detected a missense variant c.936 G>C (p. Q312H) at the end of exon 5 of LMNA by genomic DNA sequencing in 2 unrelated families affected by dilated cardiomyopathy and cardiac conduction disturbance. This variant was previously reported in a French family suffering from muscular dystrophy and cardiac conduction disturbance. Sequencing of complementary DNA demonstrated that the mutated allele was absent. By quantitative polymerase chain reaction assay, we confirmed a 90% reduction in LMNA complementary DNA. The minigene splicing reporter assay demonstrated a splicing error by the variant. Western blot analysis revealed that lamin A and C expressions were reduced far >50%. Conclusions: We report an LMNA missense mutation found in 2 families, which disrupted a normal splicing site, led to nonsense-mediated mRNA decay, and resulted in severe cardiac laminopathy.
No takes yet. Share an insight, caveat, or question.
Kato et al. (2020) conducted an observational in Dilated cardiomyopathy and cardiac conduction disturbance. LMNA missense variant c.936 G>C (p. Q312H) was evaluated on Effect of the LMNA missense mutation on RNA splicing and protein expression. The LMNA missense variant c.936 G>C (p. Q312H) disrupted a normal splicing site, leading to nonsense-mediated mRNA decay with a 90% reduction in LMNA cDNA and >50% reduction in lamin A and C.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: