The spectrum of WRN mutations in Werner syndrome patients
The spectrum of WRN mutations in Werner syndrome patients
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DOI：
10.1002/humu.20337
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发表时间：
2006-06-01
期刊：
影响因子：
3.9
通讯作者：
Oshima, Junko
中科院分区：
文献类型：
--
作者：
Huang, Shurong;Lee, Lin;Oshima, Junko
沃纳综合征国际登记处(www.wernersyndrome.org)在过去十年中一直在提供沃纳综合征(WS)的分子诊断。本通讯从99名WS受试者中总结了自1996年首次克隆WRN基因(也称为RECQL2或REQ3)以来由我们小组和其他人发现的50个不同突变的谱；其中25个以前从未发表过。到目前为止，所有已报道的WRN突变都导致了蛋白质C末端的核定位信号的消除，排除了核内的功能相互作用；因此，所有这些都可以归类为零突变。我们现在报告两个新的N端突变，导致WRN蛋白不稳定。临床资料证实最具穿透性的表型为双眼白内障。超过95%的病例可见其他主要体征。死亡年龄的中位数为54岁，此前报道的死亡年龄在46-48岁之间。淋巴母细胞系(LCL)已经从我们的大多数索引病例中被冷冻保存，包括来自核家系的材料。这些以及可诱导和补充的hTERT(人端粒酶催化亚单位)永生化皮肤成纤维细胞株可供合格的研究人员使用。
The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.