The spectrum of WRN mutations in Werner syndrome patients

Università degli Studi di Siena, Siena, Tuscany, Italy
Human Mutation (Impact Factor: 5.14). 07/2006; 27(6):558-67. DOI: 10.1002/humu.20337
Source: OAI


The International Registry of Werner syndrome ( 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.

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    • "Individuals with this syndrome develop normally until about 10 years of age and exhibit clinical symptoms in early teenage years. The mean age of survival in WS is 54 years1213. WS is more prevalent in Japan and in the Italian island of Sardinia than any other part of the world. About 1000 cases are reported in the world; more than 800 of these cases are in Japan1415. "
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    • "Werner syndrome is considered to be a model of human aging and is characterized by baldness, cataracts in the twenties, atrophy of the skin, type II diabetes mellitus usually in the thirties, arteriosclerosis in the forties, and increased incidences of malignant cancers in the mid-forties [1-3,5]. Only 1400 individuals have been diagnosed with Werner syndrome in the world and 75% of them are Japanese [5]. "
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    • "The WRN gene is associated with a disorder of premature ageing called Werner syndrome [67] and it showed evidence for positive selection under both lineage specific suites of LRTs applied in this study. The population level analysis revealed that WRN had an iHS > +2, indicating a continued positive selective pressure acting on this gene in modern humans with two independently segregating alleles in both the European (C) and African Yoruba (Y) populations (Figure 5). "
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