WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

Genetic skin diseases predisposing to basal cell carcinoma.

Basal cell carcinoma (BCC) is the commonest cancer in humans. Predisposing factors reflect common genetic variations and environmental influences in most cases. However, an underlying Mendelian disorder should be suspected in a specific subset of patients, namely those with multiple, early onset lesions. Some specific conditions, including Gorlin, Bazex-Dupré-Christol and Rombo syndromes, and Xeroderma Pigmentosum, show BCC as a prominent feature. In addition, BCC may represent a relatively common, although less specific, finding in many other genodermatoses. These include disorders of DNA replication/repair functions (Bloom, Werner, Rothmund-Thomson and Muir-Torre syndromes), genodermatoses affecting the folliculo-sebaceus unit (Brooke-Spiegler, Schöpf-Schulz-Passarge and Cowden syndromes), immune response (cartilage-hair hypoplasia and epidermodysplasia verruciformis) and melanin biosynthesis (oculocutaneous albinism and Hermansky-Pudlak syndrome), and some epidermal nevus syndromes. Further conditions occasionally associated with BCCs exist, but the significance of the association remains to be proven.

Case Report: A novel WRN mutation in Werner syndrome patient with diabetic foot disease and myelodysplastic syndrome.

Werner syndrome is an autosomal recessive rare disease caused by a WRN gene mutation, which is rarely reported in the Chinese population. We report the clinical and genetic data of a Chinese patient with Werner syndrome. The proband was a 40-year-old male patient who presented with diabetic foot ulcers, accompanied by short stature, cataracts, hypogonadism, and hair thinning, and myelodysplastic syndrome (MDS) occurred after 18 months. Genetic sequencing showed there were compound heterozygous mutations as c.3384-1G>C and c.3744dupA in the WRN gene. The c.3744dupA mutation is a novel pathogenic variation for Werner syndrome.

The Werner's Syndrome RecQ helicase/exonuclease at the nexus of cancer and aging.

Werner's Syndrome (WS) or adult-onset progeria is an autosomal recessive disorder of accelerated aging caused by mutations of the DNA RecQ helicase/exonuclease (WRN). WRN is an ATP-dependent helicase with 3' to 5' DNA exonuclease activity that regulates the replicative potential of dividing cells, and WRN loss-of-function mutations promote cellular senescence and neoplastic transformation. These molecular findings translate clinically into adult-onset progeria manifested by premature hair graying, dermal atrophy, cardiovascular disease, and cancer predilection along with a markedly reduced life expectancy. Recently, a patient with WS who developed pancreatic adenocarcinoma was identified in Honolulu suggesting a significant prevalence of loss-of-function WRN mutations in Hawaii's Japanese-American population. Based upon the indigenous Japanese WRN loss-of-function mutation heterozygote rate of 6 per 1,000, we speculate the possibility of approximately 1,200 heterozygotes in Hawaii. Our ongoing studies aim to evaluate Hawaii's true allelic prevalence of WRN loss-of-function mutations in the Japanese-American population, and the role of WRN silencing in sporadic cancers. In summary, WRN plays a nexus-like role in the complex interplay of cellular events that regulate aging, and analysis of WRN polymorphisms in Hawaii's population will generate novel insights to advance care for age-related pathologies.

The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis.

Werner syndrome (WS) is an adult onset segmental progeroid syndrome caused by mutations in the WRN gene. The WRN gene encodes a 180 kDa nuclear protein that possesses helicase and exonuclease activities. The absence of WRN protein leads to abnormalities in various DNA metabolic pathways such as DNA repair, replication and telomere maintenance. Individuals with WS generally develop normally until the third decade of life, when premature aging phenotypes and a series of age-related disorders begin to manifest. In Japan, where a founder effect has been described, the frequency of Werner heterozygotes appears to be as high as 1/180 in the general population. Due to the relatively non-specific nature of the symptoms and the lack of awareness of the condition, this disease may be under-diagnosed in other parts of the world. Genetic counseling of WS patients follows the path of other autosomal recessive disorders, with special attention needed for cancer surveillance in relatives. Molecular diagnosis of WS is made by nucleotide sequencing and, in some cases, protein analysis. It is also of potential interest to measure WRN activities in WS patients. More than 50 different disease-causing mutations in the WRN gene have been identified in WS patients from all over the world. All but one of these cases has mutations that result in the premature termination of the protein. Here we describe the clinical, molecular and biochemical characteristics of WS for use by medical professionals in a health care setting. Additional information is available through the International Registry of WS (http://www.wernersyndrome.org).

Werner's syndrome: a rare cause of hoarseness.

Werner's syndrome (WS) is a rare hereditary disorder which is characterized by clinical signs of premature aging. A 31-year-old man presented with a 12-year history of hoarseness. Also noted were diabetes mellitus, cataracts, scleroderma-like skin atrophy, osteoporosis, and hypogonadism. A clinical diagnosis of WS was made. Laryngoscopy revealed bowed vocal folds resulting in a spindle-shaped closure with glottal incompetence during phonation. We used Gortex for medialization of the middle part of vocal fold to correct the glottal gap in this patient. Despite correction of glottal incompetence in patients with WS, quality of voice could not be improved to that of age-matched normal individuals.

Recent Trends in WRN Gene Mutation Patterns in Individuals with Werner Syndrome.

OBJECTIVES: To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan. DESIGN: Retrospective cohort. SETTING: Longitudinal survey of WS and literature search for case reports. PARTICIPANTS: Individuals whose genetic testing their facilities had requested between 2009 and October 2016 (N = 67). MEASUREMENTS: A nationwide epidemiological study was conducted from 2009 to 2011 to improve understanding of the pathology of WS and develop therapeutic guidelines. Since 2009, Chiba University Hospital consecutively evaluated the WRN gene in 67 individuals throughout Japan who had requested genetic testing. A literature search was also conducted for case reports on Japanese WS reported since 1997. RESULTS: A definitive diagnosis of WS was confirmed genetically in 50 of 67 participants. Through the literature search, 16 individuals diagnosed genetically with WS were identified. Of these 66 individuals with WS, 42 were homozygous for a WRN mutation, and 21 were compound heterozygotes. One novel mutant allele was identified in an individual with the compound heterozygous genotype. The proportion of compound heterozygotes (31.8%) was significantly greater than reported previously (14.2%), indicating that the incidence of consanguineous marriage of parents has decreased. CONCLUSION: The increased frequency of individuals with WS with the compound heterozygous genotype is a recent trend in Japan. A long-term follow-up study on WRN homozygotes and compound heterozygotes will allow the relationship between WRN genotype and clinical severity of WS to be evaluated in the future.

Werner syndrome and mutations of the WRN and LMNA genes in France.

Werner syndrome (WS) is a pleiotropic disease of premature aging involving short stature, tight, atrophied, and/or ulcerated skin; a characteristic 'birdlike' facies and high, squeaky or hoarse voice; premature greying and thinning of the hair; and early onset cataracts. Additional common symptoms include diabetes mellitus, hypogonadism, osteoporosis, osteosclerosis of the digits, soft tissue calcification, premature atherosclerosis, rare or multiple neoplasms, malformed teeth, and flat feet. Diagnosis can be difficult due to the variable presentation and rarity of the disorder. Transmission is usually autosomal recessive. The WS gene, WRN, is member of the RecQ DNA helicase family. Biallelic mutations of WRN are responsible for most patients. Although heterozygous missense mutations in the LMNA gene have been observed in severely affected WS patients, this only accounts for a small fraction of non-WRN patients. Eighteen WS cases were referred to us for molecular analysis. Eleven had definite and three had probable WS according to the University of Washington Registry clinical criteria. All exons of the WRN gene and their splice junctions were sequenced. Of the fourteen definite or probable cases, 11 had one or more WRN mutation. Thirteen different mutations were found, and ten of these were previously undescribed. There were few phenotypic differences between patients with WRN mutation(s) and those who met clinical criteria though lacking WRN mutations. However, patients with mutations tended to have more symptoms overall, and mutations were not observed in the two cases with cardiomyopathy.

Excess of rare cancers in Werner syndrome (adult progeria).

The association between genetic disorders and diverse cancers has provided clues for laboratory research into carcinogenesis. Such an opportunity now arises from studies of cancer in Werner syndrome (WRN). Soft-tissue sarcoma (STS) and benign meningioma have been associated with WRN, an autosomal recessive disorder characterized by premature aging, more commonly reported in Japan than elsewhere, in part because of inbreeding. In the literature we found 124 case-reports of neoplasia and WRN from Japan and 34 from outside Japan, 1939-August, 1995. They reveal a greater diversity of neoplasia in WRN than was previously known. In Japanese, there were 127 cancers, 14 benign meningioma, and 5 myeloid disorders, as compared with 30, 7 and 2 respectively in non-Japanese. The ratio of epithelial to non-epithelial cancers was about 1:1 for Japanese and for non-Japanese instead of the usual 10:1. Both series had excess of STS, osteosarcoma, myeloid disorders, and benign meningioma. In addition, the Japanese had an excess of thyroid cancer (20 versus 2 cases in non-Japanese) and melanoma (21 versus 3 cases), including 5 intranasal and 13 of the feet. STS, osteosarcoma, melanoma, and thyroid carcinoma accounted for 57% of all cancer in WRN as compared with 2% expected based on the Osaka population at 25-64 years of age. Multiple tumors were reported in 19 Japanese and 5 non-Japanese. In Japan, nine first-degree relatives had WRN and cancer, six of whom were concordant as to site and/or cell type. The WRN gene has been mapped to chromosome 8p. The high frequency of thyroid cancer and melanoma in Japanese, not found in Caucasians, may be related to a report of linkage disequilibrium with the WRN gene in Japanese but not in Caucasians and to haplotype differences within and between the two races, suggesting multiple independent mutations.

Molecular and epidemiological studies of Werner syndrome in the Japanese population.

Werner syndrome (WS) is an autosomal recessive genetic disease characterized by many age-related features. The gene responsible for WS (WRN) has been isolated and contains a helicase domain, but its function is unknown. Six different mutations throughout the WRN gene have been reported in the Japanese population. We have studied whether patients with a specific mutation exhibit distinct phenotypes from others. Fourteen patients with different mutations showed almost the same signs and symptoms and, therefore, the C terminal part of the product appears to be crucial for its functions, although other parts may be important as well. Haplotype analyses using 13 microsatellites covering the 2.8-3.0 cM WRN region showed that two out of six different mutations had founder chromosomes. These two founder chromosomes may be evenly distributed throughout the western part of Japan, suggesting that these mutations go back to a time earlier than 1400 years ago.

Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population.

The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus (NIDDM), ocular cataracts and osteoporosis [Epstein et al., 1966]. The major cause of death (at a median age of 47) is myocardial infarction (MI) [Epstein et al., 1966]. The WS mutation involves a member (WRN) of the RecQ family of helicases and may perturb DNA replication, repair, recombination, transcription, or chromosomal segregation [Yu et al., 1996]. We now report data on 149 MI cases and age-matched controls suggesting that a polymorphic WRN variant is associated with increased risk for MI. Based on our data, homozygosity for a cysteine at amino acid 1367 (the most prevalent genotype) predicts a 2.78 times greater risk of MI (95% confidence intervals: 1.23 to 6.86). The variant was not significantly associated with NIDDM. The two alleles (cysteine vs. arginine) could influence helicase activity, turnover, macromolecular interactions or, alternatively, could be markers for haplotypes influencing WRN regulation or reflecting gene action at linked loci. However, given the caveats implicit in genetic association studies, it is imperative that the present results be replicated in independent populations.

Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis.

Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the WRN locus. The WRN gene encodes a nuclear protein of 180 kD that contains both exonuclease and helicase domains. WS patients develop various forms of arteriosclerosis, particularly atherosclerosis, and medial calcinosis. The most common cause of death in Caucasian subjects with WS is myocardial infarction. Previous studies have identified specific polymorphisms within WRN that may modulate the risk of atherosclerosis. Population studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertaken to evaluate the role of WRN in atherogenesis. Frequencies of the 1074Leu/Phe polymorphisms in Finnish and Mexican populations revealed an age-dependent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finnish newborns, the 1074Leu/Phe and 1367Cys/ Arg polymorphisms were in linkage disequilibrium. Among coronary artery disease subjects, there was a tendency for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lower degree of coronary artery occlusion, as measured by NV50, when compared to the 1367Cys/Cys or 1367Cys/Arg genotypes. However, these tendencies did not achieve statistical significance. Samples from Mexican patients with ischemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis that WRN may mediate not only WS, but may also modulate more common age-related disorders and, perhaps, a basic aging process.

Clinical, demographic, and genetic aspects of the Werner syndrome in Japan.

A total of 196 typical patients with the Werner syndrome, a caricature of aging, was studied to define the details of the clinical manifestations, demography and genetic aspects in Japan. Most of the previously reported clinical characteristics and the autosomal recessive inheritance of this syndrome were confirmed, but no significant linkage was revealed between specific HLA type and the Werner syndrome. The frequency of the Werner syndrome in Japan was estimated using two methods which indicated approximately 300 cases among 100 million people.

Spectrum and risk of neoplasia in Werner syndrome: a systematic review.

BACKGROUND: Werner syndrome (WS) is an autosomal recessive genetic instability and progeroid ('premature aging') syndrome which is associated with an elevated risk of cancer. OBJECTIVES: Our study objectives were to characterize the spectrum of neoplasia in WS using a well-documented study population, and to estimate the type-specific risk of neoplasia in WS relative to the general population. METHODS: We obtained case reports of neoplasms in WS patients through examining previous case series and reviews of WS, as well as through database searching in PubMed, Google Scholar, and J-EAST, a search engine for articles from Japan. We defined the spectrum (types and sites) of neoplasia in WS using all case reports, and were able to determine neoplasm type-specific risk in Japan WS patients by calculating standardized incidence and proportionate incidence ratios (SIR and SPIR, respectively) relative to Osaka Japan prefecture incidence rates. RESULTS: We used a newly assembled study population of 189 WS patients with 248 neoplasms to define the spectrum of neoplasia in WS. The most frequent neoplasms in WS patients, representing 2/3 of all reports, were thyroid neoplasms, malignant melanoma, meningioma, soft tissue sarcomas, leukemia and pre-leukemic conditions of the bone marrow, and primary bone neoplasms. Cancer risk defined by SIRs was significantly elevated in Japan-resident WS patients for the six most frequent neoplasms except leukemia, ranging from 53.5-fold for melanoma of the skin (95% CI: 24.5, 101.6) to 8.9 (95% CI: 4.9, 15.0) for thyroid neoplasms. Cancer risk as defined by SPIR was also significantly elevated for the most common malignancies except leukemia. CONCLUSIONS: WS confers a strong predisposition to several specific types of neoplasia. These results serve as a guide for WS clinical care, and for additional analyses to define the mechanistic basis for cancer in WS and the general population.

Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008).

As ~75% of the Werner syndrome (WS) patients recognized between 1904 and 2008 all over the world are of Japanese origin, the most case reports and clinical studies on WS has been published in Japanese journals. Thus, the detailed English-written clinical review on the recent WS case reports has been warranted. Although WS has been characterized by a variety of clinical manifestations mimicking premature aging, the recent longevity and delayed age-associated manifestations observed both from Japanese WS and general population may suggest a common environmental effect on some gene(s) other than WRN and may give us a newer pathophysiological look at WS and also natural aging through the molecular dysfunction of WRN.

Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey.

AIM: Werner syndrome (WS) is an autosomal recessive disorder of progeroid symptoms and signs. It is caused by mutations in the WRN gene, which encodes a RecQ DNA helicase. The aim of this study was to revise the diagnostic criteria for Japanese Werner syndrome. METHODS: A nationwide epidemiological study was carried out from 2009 to 2011, involving 6921 surveys sent to hospitals with more than 200 beds to assess existing WS diagnostic criteria, as well as additional signs of high incidence on the basis of clinical experience with WS. RESULTS: The existing diagnostic criteria were reviewed, and signs with >90% incidence were listed as cardinal signs. Several criteria were added, including genetic testing and calcification of the Achilles tendon, whereas criteria that are practically difficult to obtain, such as measurement of urinary hyaluronic acid, were omitted. CONCLUSION: The 26-year-old diagnostic criteria for WS were revised on the basis of the results of a nationwide epidemiological study. The proposed revised criteria will facilitate simpler, faster and more robust diagnosis of WS in the Japanese population.