A novel Werner Syndrome mutation: pharmacological treatment by read-through of nonsense mutations and epigenetic therapies.

Abstract

Werner Syndrome (WS) is a rare inherited disease characterized by premature aging and increased propensity for cancer. Mutations in the WRN gene can be of several types, including nonsense mutations, leading to a truncated protein form. WRN is a RecQ family member with both helicase and exonuclease activities, and it participates in several cell metabolic pathways, including DNA replication, DNA repair, and telomere maintenance. Here, we reported a novel homozygous WS mutation (c.3767 C > G) in 2 Argentinian brothers, which resulted in a stop codon and a truncated protein (p.S1256X). We also observed increased WRN promoter methylation in the cells of patients and decreased messenger WRN RNA (WRN mRNA) expression. Finally, we showed that the read-through of nonsense mutation pharmacologic treatment with both aminoglycosides (AGs) and ataluren (PTC-124) in these cells restores full-length protein expression and WRN functionality.

• Authors: Ruben Agrelo, Miguel Arocena Sutz, Fernando Setien, Fabian Aldunate, Manel Esteller, Valeria Da Costa, Ricardo Achenbach
• Journal: Epigenetics (Epigenetics) Vol. 10 Issue 4 Pg. 329-41 ( 2015) ISSN: 1559-2308 [Electronic] United States
• PMID: 25830902 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoglycosides
• Codon, Nonsense
• Oxadiazoles
• Protein Synthesis Inhibitors
• ataluren

Topics

• Aging, Premature (genetics)
• Aminoglycosides (pharmacology)
• Apoptosis (drug effects)
• Cells, Cultured
• Chromosomes, Human (drug effects)
• Codon, Nonsense
• DNA Damage (drug effects)
• DNA Methylation (drug effects)
• DNA Replication (drug effects)
• Epigenesis, Genetic
• Female
• Humans
• Male
• Mutation
• Oxadiazoles (pharmacology)
• Promoter Regions, Genetic (drug effects)
• Protein Synthesis Inhibitors (pharmacology)
• Werner Syndrome (drug therapy, genetics)