Centre de recherche du CHU de Québec, Pavillon CHUL Université Laval, Faculté de Médecine, Québec City, Québec, G1V 4G2, Canada.
Departments of Pathology and Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Ageing Res Rev. 2018 Jan;41:82-97. doi: 10.1016/j.arr.2017.11.003. Epub 2017 Nov 14.
Werner syndrome (WS) is a heritable autosomal recessive human disorder characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients, WRN, is encoded by a member of the human RECQ gene family that contains both a DNA exonuclease and a helicase domain. WRN has been shown to participate in several DNA metabolic pathways including DNA replication, recombination and repair, as well as telomere maintenance and transcription modulation. Here we review base pair-level genetic variation that has been documented in WRN, with an emphasis on non-synonymous coding single nucleotide polymorphisms (SNPs) and their associations with anthropomorphic features, longevity and disease risk. These associations have been challenging to identify, as many reported WRN SNP associations appear to be further conditioned upon ethnic, age, gender or other environmental co-variables. The WRN variant phenotypic associations identified to date are intriguing, and several are of clear clinical import. Consequently, it will be important to extend these initial associations and to identify the mechanisms and conditions under which specific WRN variants may compromise WRN function to drive cellular and organismal phenotypes as well as disease risk.
Werner 综合征（WS）是一种遗传性常染色体隐性人类疾病，其特征是多种与年龄相关的病理的过早发生，包括癌症。在 WS 患者中缺陷的蛋白，WRN，由人类 RECQ 基因家族的一员编码，该基因家族既包含 DNA 外切酶又包含解旋酶结构域。WRN 已被证明参与了几种 DNA 代谢途径，包括 DNA 复制、重组和修复，以及端粒维持和转录调节。在这里，我们回顾了 WRN 中记录的碱基对水平的遗传变异，重点介绍了非同义编码单核苷酸多态性（SNPs）及其与人体形态特征、长寿和疾病风险的关联。这些关联很难确定，因为许多报道的 WRN SNP 关联似乎进一步取决于种族、年龄、性别或其他环境协变量。迄今为止，已经确定了与 WRN 变异表型相关的几个有趣的关联，其中一些具有明显的临床意义。因此，扩展这些初始关联并确定特定 WRN 变体在何种机制和条件下可能会损害 WRN 功能，以驱动细胞和机体表型以及疾病风险，将是很重要的。
