Werner syndrome gene variants in human sarcomas.
Werner syndrome gene variants in human sarcomas.
复制标题
人类肉瘤中的维尔纳综合征基因变异。
DOI：
10.1002/mc.20586
复制
发表时间：
2010
影响因子：
4.6
通讯作者：
Loeb,LawrenceA
中科院分区：
文献类型：
--
作者：
Hsu,JessicaJ;Kamath-Loeb,AshwiniS;Glick,Eitan;Wallden,Brett;Swisshelm,Karen;Rubin,BrianP;Loeb,LawrenceA
沃纳综合征是一种常染色体遗传性疾病，其特征是过早衰老。Werner综合征（WS）中突变的基因WRN编码3′ → 5′ DNA解旋酶和3′ → 5′ DNA外切酶。在WS表型中，肉瘤的发病率异常高。我们询问了自发性肉瘤是否也存在WRN突变或未报道的单核苷酸多态性（SNPs）。我们分析了RNA或DNA序列内的解旋酶和核酸外切酶域分别从51和69匹配肉瘤和邻近的正常组织。在总共检测到的13个核苷酸变体中，我们鉴定了三个新的非同义替换：c.611C>T，c.809_810insT和c.1882C>G。我们进一步表征了一个，c.611C>T，其导致外切核酸酶结构域中氨基酸204处进化上保守的脯氨酸被亮氨酸取代。我们发现P204 L WRN表现出WRN核酸外切酶活性的降低;比活性比野生型WRN低10倍。相反，P204 L WRN的解旋酶活性降低不到两倍。© 2009 Wiley利斯公司
Werner syndrome is an autosomal inherited disease that is characterized by premature aging. The gene mutated in Werner syndrome (WS),WRN, encodes both a 3′ → 5′ DNA helicase and a 3′ → 5′ DNA exonuclease. Among the WS phenotypes is an exceptionally high incidence of sarcomas. We asked whether spontaneous sarcomas, not known to be associated with WS, also harbor mutations or unreported single nucleotide polymorphisms (SNPs) inWRN. We analyzed RNA or DNA sequences within the helicase and exonuclease domains from 51 and 69 matched sarcoma and adjacent normal tissues, respectively. Among a total of 13 nucleotide variants detected, we identified three novel nonsynonymous substitutions: c.611C>T, c.809_810insT, and c.1882C>G. We further characterized one, c.611C>T, which results in substitution of an evolutionarily conserved proline at amino acid 204 in the exonuclease domain with leucine. We show that P204L WRN exhibits a reduction of WRN exonuclease activity; the specific activity is ∼10‐fold lower than that of wild‐type WRN. In contrast, the helicase activity of P204L WRN is reduced less than twofold. © 2009 Wiley‐Liss, Inc.