The spectrum of WRN mutations in Werner syndrome patients

Department of Pathology, University of Washington, Seattle, Washington 98195-7470, USA.
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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    ABSTRACT: Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs). As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent 'drug of hope' for Hutchinson-Gilford progeria syndrome (HGPS) and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs.
    The Indian Journal of Medical Research 05/2014; 139(5):667-74. · 1.40 Impact Factor
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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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    ABSTRACT: To present our findings in a case of Werner syndrome with refractory cystoid macular edema (CME) and to determine the expression and the distribution of WRN proteins in human retinas. A 35-year-old man with Werner syndrome who developed CME after YAG laser treatment was studied. Optical coherence tomographic (OCT) scans were used to examine the CME in the right eye. The patient received topical eye drops (0.1% bromfenac sodium hydrate twice daily and 1% dorzolamide hydrochloride thrice daily), sub-Tenon triamcinolone injection thrice, intravitreal bevacizumab injection twice, and pars plana vitrectomy of the right eye. Genetic analyses were performed to diagnose the disease. To examine the expression and distribution of WRN proteins in the retinas, immunohistochemistry for WRN proteins was performed in human retinas. The CME in the right eye was not improved by any of the treatments. During the follow-up period, CME developed in the left eye. Genetic analyses detected compound heterozygosity, Mut4 and Mut11, in the WRN gene and the individual was diagnosed with Werner syndrome. Immunohistochemical analysis of WRN proteins expression in human retinas showed that WRN proteins were expressed in the parts of the Muller cells in the inner nuclear layer and outer nuclear layer. Patients with Werner syndrome can develop severe CME after laser treatment. A pathological link may exist between mutations in the WRN gene and the development of CME in patients with Werner syndrome.
    BMC Ophthalmology 03/2014; 14(1):31. DOI:10.1186/1471-2415-14-31 · 1.02 Impact Factor
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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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