W erner syndrome (WS) (MIM#277700) is an uncommon autoso- mal recessive disease whose phenotype includes progeroid features, constitutional genetic instability, and an elevated risk of selected neoplasms including thyroid carcinoma. 1,2 In their recent article 3 Ishikawa et al. suggested that the different spectrum of mutations in the WS gene (WRN) in Japanese WS patients may confer a higher risk of thyroid carcinoma, and that N-and C-terminal WRN mutations may favor papillary or follicular thyroid carcinoma histology, respectively. These suggestions are intriguing but recent results suggest they are unlikely to be correct.
Both of these suggestions assume that different mutant WRN alleles encode truncated mutant proteins that retain different amounts or combinations of WRN nuclease and RecQ helicase consensus domains although lack a C-terminal nuclear localization signal. 4 However, recent results from our laboratory in Seattle and the laboratory of Dr. Ishikawa's colleagues at the AGENE Research Institute in Kanagawa 5 indicate that WS patient cell lines lack detectable mutant protein by two different criteria. These analyses included Japanese mutations 4 and 6, which together represent 80% of the WRN mutations identified in Japanese WS patients (unpublished data). 5 Thus many (and perhaps all) WS-associated WRN mutations are likely to be functionally equivalent null alleles. These results make it unlikely that a different spectrum of WRN mutations alone explains the elevated risk of thyroid carcinoma in Japanese WS patients. However, the consistent absence of WRN protein from WS patient cells could both favor and partially explain the development of thyroid carcinomas with follicular or anaplastic, as opposed to the more common papillary, histology. These issues should be clarified further when more is known regarding WRN function and genetic modifiers of WRN functional pathways in human somatic cells and in animal models of WS.
A second issue, related to Table 4 in the article by Ishikawa et al. 3 , is that a Web-accessible, locus specific mutational database for WSassociated WRN mutations currently is available. This database, established as part of the HUGO Locus-Specific Mutational Database Initiative, updates and corrects some of the data presented in Table 4 and includes additional WRN mutation and polymorphism data. The database uses a systematic nomenclature to describe WRN mutations and polymorphisms and is cross-referenced and linked to Web sites for the Human Gene Mutation Database and Online Mendelian Inheritance in Man. There also is a link to the International Registry of Werner Syndrome at the University of Washington, where WS diagnostic and pathology consulting assistance can be obtained. The URL for the WRN Mutational Database is http://www.pathology.washing ton.edu/werner/.