RESUMO

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.

Assuntos

Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Mutação , Síndrome de Werner/genética , Senilidade Prematura/genética , Aminoglicosídeos/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Cromossomos Humanos/efeitos dos fármacos , Códon sem Sentido , Dano ao DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Feminino , Humanos , Masculino , Oxidiazóis/farmacologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Síndrome de Werner/tratamento farmacológico