Processing of OPA1 with a novel N-terminal mutation in patients with autosomal dominant optic atrophy: Escape from nonsense-mediated decay

PLoS One. 2017 Aug 25;12(8):e0183866. doi: 10.1371/journal.pone.0183866. eCollection 2017.

Abstract

Autosomal Dominant Optic Atrophy (ADOA) is the most common dominantly inherited optic neuropathy. In the majority of patients it is caused by OPA1 mutations and those predicted to introduce a premature termination codon (PTC) are frequently detected. Transcripts containing PTC may be degraded by nonsense-mediated mRNA decay (NMD), however very little is known about an effect of OPA1 mutations on NMD activation. Here, using a combination of linkage analysis and DNA sequencing, we have identified a novel c.91C>T OPA1 mutation with a putative premature stop codon (Q31*), which segregated with ADOA in two Polish families. At the mRNA level we found no changes in the amount of OPA1 transcript among mutation carriers vs. non-carriers. Specific allele quantification revealed a considerable level of the OPA1 mutant transcript. Our study identifies a novel pathogenic OPA1 mutation and shows that it is located in the transcript region not prone for NMD activation. The data emphasizes the importance of analyzing how mutated genes are being processed in the cell. This gives an insight into the molecular mechanism of a genetic disease and promotes development of innovative therapeutic approaches.

MeSH terms

  • Codon, Terminator
  • Female
  • GTP Phosphohydrolases / genetics*
  • Genetic Carrier Screening
  • Genetic Linkage
  • Humans
  • Male
  • Microsatellite Repeats / genetics
  • Mutation*
  • Nonsense Mediated mRNA Decay*
  • Optic Atrophy, Autosomal Dominant / genetics*
  • Pedigree
  • RNA, Messenger / genetics

Substances

  • Codon, Terminator
  • RNA, Messenger
  • GTP Phosphohydrolases
  • OPA1 protein, human

Grants and funding

The work was supported by Narodowe Centrum Nauki (National Science Center of Poland, NCN) grant no. N N402 591540 (5915/B/P01/2011/40)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.