Agrelo Ruben, Sutz Miguel Arocena, Setien Fernando, Aldunate Fabian, Esteller Manel, Da Costa Valeria, Achenbach Ricardo
a Epigenetics of Cancer and Aging Laboratory Institut Pasteur de Montevideo (IPMON) ; Montevideo , Uruguay.
Epigenetics. 2015;10(4):329-41. doi: 10.1080/15592294.2015.1027853.
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.
沃纳综合征（WS）是一种罕见的遗传性疾病，其特征为早衰和患癌倾向增加。WRN基因的突变有多种类型，包括无义突变，可导致截短的蛋白质形式。WRN是RecQ家族成员，具有解旋酶和核酸外切酶活性，它参与多种细胞代谢途径，包括DNA复制、DNA修复和端粒维持。在此，我们报道了2名阿根廷兄弟中一种新的纯合WS突变（c.3767 C>G），该突变导致一个终止密码子和截短的蛋白质（p.S1256X）。我们还观察到患者细胞中WRN启动子甲基化增加，以及信使WRN RNA（WRN mRNA）表达降低。最后，我们表明，在这些细胞中用氨基糖苷类药物（AGs）和阿他芦醇（PTC-124）对无义突变进行通读药物治疗可恢复全长蛋白质表达和WRN功能。
