Epigenetics. 2015 Apr 1:0. [Epub ahead of print]
A novel Werner Syndrome mutation: Pharmacological treatment by read-through of nonsense mutations and epigenetic therapies.
Agrelo R1, Arocena Sutz M, Setien F, Aldunate F, Esteller M, Da Costa V, Achenbach R.
1a Epigenetics of Cancer and Aging Laboratory Institut Pasteur de Montevideo(IPMON) , Mataojo 2020, 1140 Montevideo , Uruguay
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 two 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. |
