title: 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.affiliation: a Epigenetics of Cancer and Aging Laboratory Institut Pasteur de Montevideo (IPMON) ; Montevideo , Uruguay.
authors.forename: Ruben
authors.initials: R
authors.lastname: Agrelo
authors.forename: Miguel Arocena
authors.initials: MA
authors.lastname: Sutz
authors.forename: Fernando
authors.initials: F
authors.lastname: Setien
authors.forename: Fabian
authors.initials: F
authors.lastname: Aldunate
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Valeria
authors.initials: V
authors.lastname: Da Costa
authors.forename: Ricardo
authors.initials: R
authors.lastname: Achenbach
mesh_terms: D019588:Aging, Premature / Q000235:genetics; D000617:Aminoglycosides / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002877:Chromosomes, Human / Q000187:drug effects; D018389:Codon, Nonsense; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010069:Oxadiazoles / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014898:Werner Syndrome / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000617:Aminoglycosides; D018389:Codon, Nonsense; D010069:Oxadiazoles; D011500:Protein Synthesis Inhibitors; C515878:ataluren
keywords: Epigenetics; PTC read-through therapy; Werner Syndrome; methylation; mutation
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