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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first sign is the lack of a growth spurt during the early teen years. Early findings (usually observed in the 20s) include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Myocardial infarction and cancer are the most common causes of death, typically at about age 48 years.
Diagnosis/testing. Clinical diagnostic criteria have been proposed. WRN is the only gene known to be associated with Werner syndrome. Mutations in WRN are identified in approximately 90% of individuals with Werner syndrome. Molecular genetic testing for the WRN gene is available on a research basis only.
Management. Treatment of manifestations: aggressive treatment of skin ulcers; control of type 2 diabetes mellitus (pioglitazone has been successful); cholesterol-lowering drugs if lipid profile is abnormal; surgical treatment of ocular cataracts using special techniques; treatment of malignancies in a standard fashion. Prevention of secondary complications: smoking avoidance, regular exercise, weight control to reduce atherosclerosis risk; excellent skin care and avoidance of trauma to the skin. Surveillance: screening for type 2 diabetes mellitus at least annually; annual lipid profile; at least annual physical examination with attention to malignancies common in Werner syndrome; annual ophthalmologic examination for cataracts; attention to signs of angina. Agents/circumstances to avoid: smoking and excess weight to help reduce the risk of atherosclerosis; trauma to the extremities.
Genetic counseling. Werner syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Prenatal testing for WRN mutations may be available through laboratories offering custom prenatal testing.
The following diagnostic criteria have been proposed for Werner syndrome [modified from Nakura et al 1994]:
Cardinal signs and symptoms (onset after age ten years)
Bilateral cataracts
Characteristic skin (tight skin, atrophic skin, pigmentary alterations, ulceration, hyperkeratosis, regional subcutaneous atrophy)
Characteristic facies that have been described as "bird-like" (i.e., the nasal bridge appears pinched and subcutaneous tissue is diminished)
Short stature
Premature graying and/or thinning of scalp hair
Parental consanguinity (third cousin or closer) or affected sibling
Further signs and symptoms
Type 2 diabetes mellitus
Hypogonadism (secondary sexual underdevelopment, diminished fertility, testicular or ovarian atrophy)
Osteoporosis
Radiographic evidence of osteosclerosis of distal phalanges of fingers and/or toes
Soft-tissue calcification
Evidence of premature atherosclerosis (e.g., history of myocardial infarction)
Neoplasms: mesenchymal (i.e., sarcomas), rare (e.g., unusual sites of melanomas and osteosarcomas [Goto et al 1996, Ishikawa et al 2000]), or multiple
Abnormal voice (high-pitched, squeaky, or hoarse [Tsunoda et al 2000])
Flat feet
The International Registry of Werner Syndrome uses the above findings to establish a "definite," "probable," or "possible" diagnosis pending molecular genetic confirmation. Any set of diagnostic criteria is imperfect, especially when a question of Werner syndrome is posed about a young person before many of the symptoms would manifest.
Definite diagnosis: all of the cardinal signs and two others
Probable diagnosis: the first three cardinal signs and any two others
Possible diagnosis: either cataracts or dermatologic alterations and any four others
Exclusion of the diagnosis: onset of cardinal signs and further symptoms before age ten years, except for short stature, which is typically caused by lack of the usual adolescent growth spurt
Goto (1997) proposed the clinical diagnosis of Werner syndrome if at least four of the following findings are present:
Consanguinity
Characteristic facial appearance and body habitus
Premature senescence
Scleroderma-like skin changes
Endocrine-metabolic disorders
Urinary and serum concentration of hyaluronic acid may be increased in some individuals with Werner syndrome [Tollefsbol & Cohen 1984, Goto 1997, Tanabe & Goto 2001]. Although an increase in urinary hyaluronic acid was used in the past to support the diagnosis of Werner syndrome, this testing is cumbersome and nonspecific, and thus not recommended.
Variegated translocation mosaicism. An increase in structural, but not numeric, chromosomal aberrations has been observed in lymphocyte and fibroblast cultures. Chromosomal aberrations (variegated translocation mosaicism) as a result of spontaneous chromosome instability has been observed in cells of individuals with Werner syndrome [Hoehn et al 1975, Grigorova et al 2000], but this finding is not diagnostic.
Heterozygotes. Cells isolated from individuals heterozygous for WRN mutations have shown intermediate sensitivity to the genotoxic agent 4-nitroquinoline oxide [Ogburn et al 1997].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. WRN is the only gene known to be associated with Werner syndrome.
Other loci. No other loci associated with typical forms of Werner syndrome have been identified, but it is possible that mutations in genes encoding proteins that interact with WRN may produce a similar phenotype.
Research testing
Sequence analysis. Sequence analysis of the WRN coding region detects mutations in both alleles for approximately 90% of affected individuals. No single WRN mutation predominates in Caucasian individuals affected with Werner syndrome [Oshima et al 1996, Yu et al 1997, Huang et al 2006]. Mutations may occur within the relatively large introns and regulatory regions; these are not routinely analyzed.
Western blot analysis. Following the identification of a mutation by sequence analysis, Western blot analysis is used to determine the effect of the mutation on the WRN protein. In the majority of affected individuals, WRN mutations result in the absence of protein on Western blot analysis (truncated protein may be detected in rare cases) or immunoblot analysis [Goto et al 1999, Shimizu et al 2002].
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|
| Sequence analysis | WRN sequence variants | ~90% | Research only 2 |
1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method
2. Additional information about research studies may be obtained at the International Registry of Werner Syndrome.
Werner syndrome is the only phenotype associated with WRN mutations. Bloom syndrome and Rothmund-Thomson syndrome are caused by mutations in closely related but distinct helicase genes.
Atypical Werner syndrome is caused by mutations in the LMNA gene (see Differential Diagnosis).
Werner syndrome is characterized clinically by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first symptom, often recognized retrospectively, is the lack of a growth spurt during the early teen years.
The male:female ratio is believed to be 1:1. In the International Registry of Werner Syndrome, females are slightly over-represented, probably because of ascertainment bias; women are more likely than men to present for medical care and tend to have more concern about a youthful appearance.
Symptoms typically start in the 20s. The youngest patient with a molecular confirmation of the diagnosis was age six years [Huang et al 2006]. Initial findings include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Median age of diagnosis was 38 years in three studies [Epstein et al 1966; review by Tollefsbol & Cohen 1984, Goto 1997]. A characteristic facial appearance, termed "bird-like" because of the pinched appearance at the bridge of the nose, evolves during the third or fourth decade.
Affected individuals exhibit several forms of arteriosclerosis; the most serious form, coronary artery atherosclerosis, may lead to myocardial infarction which, together with cancer, is the most common cause of death. The mean age of death in individuals with Werner syndrome is 54 years. The mean age of diagnosis is 46 years.
The spectrum of cancers in individuals with Werner syndrome is unusual in that it includes a large number of sarcomas and very rare types of cancers in typical locations [Goto et al 1996, Yamamoto et al 2003]. The most common cancers in Japanese individuals (for whom the most data exist) are soft-tissue sarcomas, osteosarcomas, melanomas, and thyroid carcinomas. Acral lentiginous melanomas (most often observed on the feet and nasal mucosa) are particularly prevalent compared to levels observed the general population [Goto et al 1996].
The osteoporosis of individuals with Werner syndrome is unusual in that it especially affects the long bones. In contrast, osteoporosis during normative aging preferentially involves the vertebral bodies, particularly in females. Characteristic osteolytic lesions of the distal joints of the fingers are observed on radiograph.
Deep, chronic ulcers around the ankles (Achilles tendons, medial malleolus, lateral malleolus) are highly characteristic.
Controversy exists concerning the degree to which the brain is involved. While individuals with Werner syndrome may have central nervous system complications of arteriosclerosis, they do not appear to be unusually susceptible to Alzheimer disease [Martin et al 1999]. Cognitive changes are not typically observed. Diffuse changes observed on brain MRI in some individuals warrant further investigation in research studies [De Stefano et al 2003].
Fertility. Fertility appears to decline soon after sexual maturity. This decline in fertility is associated with testicular atrophy and probable accelerated rate of loss of primoridial follicles in the ovaries, although data are sparse. Early menopause is common in women as are multiple miscarriages, but successful pregnancies have also been reported. Men have fathered children, usually at younger ages [Epstein et al 1966].
The chronologic order of the onset of signs and symptoms is similar in all individuals with Werner syndrome regardless of the specific WRN mutations [Epstein et al 1966, review by Tollefsbol & Cohen 1984, Goto 1997].
The specific cell type in which cancer develops may depend on the type of WRN mutation present. In individuals of Japanese descent, papillary carcinoma has been associated with an N-terminal mutation, whereas follicular carcinoma is more frequently observed with a C-terminal mutation [Ishikawa et al 1999]. This finding clearly contradicts the original assumption that all identified WRN mutations result in truncation of the nuclear localization signal of WRNp and thereby act as null mutations. Further studies may reveal additional genotype-phenotype correlations.
Another name for Werner syndrome is 'progeria of the adult' (to distinguish it from the Hutchinson-Gilford progeria syndrome, which is often referred to as progeria of childhood).
The prevalence of Werner syndrome varies with the level of consanguinity in populations.
In the Japanese population, the frequency ranges from about 1:20,000 to 1:40,000, based upon the frequencies of detectable heterozygous mutations [Satoh et al 1999]. This is most likely the result of a founder mutation in the Japanese population.
The prevalence in the US population is unknown, but may be of the order of 1:200,000 [Martin et al 1999].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The differential diagnosis depends on the presenting symptoms and age of onset.
Atypical Werner syndrome refers to a small subset of individuals included in the Werner Syndrome Registry who have normal WRN protein and some signs and symptoms that sufficiently overlap with the Werner syndrome such that clinicians submit these cases to the International Registry. These individuals can give a history of comparatively early age of onset (early 20s or earlier) and a faster rate of progression than those with typical Werner syndrome. Among this group, four of 26 individuals (15%) had novel heterozygous missense mutations in LMNA [Chen et al 2003].
Mandibulo-acral dysplasia (MAD) is a progeroid syndrome characterized by short stature; thin, hyperpigmented skin; partial alopecia; prominent eyes; beaked nose; tooth loss; small recessed chin, and short fingers [Cavallazzi et al 1960, Cohen et al 1973]. Mutations in the LMNA gene have been reported by Novelli et al (2002). A 28-year-old woman with mandibuloacral dysplasia, previously diagnosed as "atypical progeria," was found to have a compound heterozygous mutation (p.Arg471Cys in exon 8/p.Arg527Cys in exon 9) [Cao & Hegele 2003]. Inheritance is autosomal recessive.
Hutchinson-Gilford progeria syndrome (HGPS or progeria of childhood), like Werner syndrome, affects multiple organs with presentations characterized as accelerated aging. Newborns with HGPS usually appear normal, but profound failure to thrive occurs during the first year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the second to third year. Motor and mental development is normal. Individuals with HGPS develop severe atherosclerosis. Death usually occurs as a result of complications of cardiac or cerebrovascular disease generally between age six and 20 years. Average life span is approximately 13 years. About 90% of individuals with HGPS have the same p.Gly608Gly mutation in exon 11. Inheritance is autosomal dominant. All individuals with HGPS have a de novo mutation.
Early-onset type 2 diabetes with secondary complications of vascular disease and skin complications could mimic some features of Werner syndrome.
Though bilateral ocular cataracts (probably presenting as posterior subcapsular cataracts) are one of the most commonly observed features of Werner syndrome, the age of onset is typically in the second decade when graying of hair and skin findings would likely be present. Isolated juvenile cataracts are therefore not likely to be a feature of Werner syndrome. Myotonic dystrophy type 1 or myotonic dystrophy type 2 could be a consideration with young adult-onset cataracts, and adults may show muscle wasting although other manifestations (myotonia, cardiac conduction abnormalities) are quite different and onset is usually in adulthood.
Scleroderma, mixed connective tissue disorders, and lipodystrophy may present skin features similar to those of Werner syndrome. Distal atrophy and skin ulcerations in the absence of other manifestations characteristic of Werner syndrome could raise the possibility of Charcot-Marie-Tooth disease or familial leg ulcers of juvenile onset.
Other cancer-prone syndromes, including Rothmund-Thomson syndrome (RTS) (caused by mutations in RECQL4), and Bloom syndrome (caused by mutations in BLM) may be considered if cancer is the presenting symptom. However, RTS and Bloom syndrome are childhood-onset disorders. Werner syndrome cells do not exhibit the increased sister chromatid exchange typical of Bloom syndrome. Li-Fraumeni syndrome (caused by mutations in TP53) may present multiple cancers, including non-epithelial cancers similar to those observed in Werner syndrome, but juvenile-onset cataracts and other manifestations of Werner syndrome are not part of Li-Fraumeni syndrome.
The following conditions share at least two features of Werner syndrome, but are less likely to be confused with the condition because they are characterized by onset in childhood and additional characteristic features.
The Flynn-Aird syndrome includes cataracts combined with skin atrophy and ulceration, but neural abnormalities are also present [Flynn & Aird 1965].
The branchiooculofacial syndrome is characterized by premature graying in adults. Eye findings typically include strabismus, coloboma, and micropthalmia. Dysmorphic facial features are also present.
The SHORT syndrome (short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay) may have progeria-like facies and lipodystrophy. Type 2 diabetes mellitus, as well as cataracts and glaucoma, have been reported in affected individuals [Schwingshandl et al 1993, Sorge et al 1996].
To establish the extent of disease in an individual diagnosed with Werner syndrome, the following evaluations are recommended:
Screen for type 2 diabetes mellitus by standard clinical assays
Lipid profiles
Physical examination for cancers common in Werner syndrome, (e.g., thyroid nodules, skin tumors)
Ophthalmologic examination including slit lamp examination
Skin examination for common findings, especially early ulcerations of the feet, with special attention to nail beds and soles of feet for lentiginous melanoma
MRI if neurologic symptoms are present (e.g., chronic headaches that could suggest a diagnosis of meningioma, a common neoplasm in Werner syndrome)
Assessment of coping and psychological fitness in light of prognosis
Aggressive treatment of skin ulcers with standard or novel techniques [Akiyama et al 2000, Yamamoto et al 2003, Yeong & Yang 2004]
Control of type 2 diabetes mellitus. Favorable results have been reported with use of pioglitazone [Imano et al 1997, Durbin 2004, Yokote et al 2004].
Use of cholesterol-lowering drugs if lipid profile is abnormal. Muscle atrophy is a potential complication
Surgical treatment of ocular cataracts. Complications are common and specific techniques can optimize outcome [Shintani et al 1993, Ruprecht 1989].
Treatment of malignancies in a standard fashion
Lifestyle counseling for smoking avoidance, regular exercise, and weight control to reduce atherosclerosis risk
Excellent skin care, trauma avoidance, and examination to treat problems early
Screening for type 2 diabetes mellitus at least annually
Annual lipid profile
At least annual physical examination seeking malignancies common in Werner syndrome and other skin manifestations
Annual ophthalmologic examination for cataracts
Attention to signs of angina
Smoking and excess weight, which increase the risk of atherosclerosis
Trauma to the extremities
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Affected individuals may benefit from reproductive advice regarding the rapid decline of fertility.
Although topical PDGF-BB has been shown to provide some improvement of granulation, it failed to heal the ulcer in a person with Werner syndrome [Wollina et al 2004].
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Werner syndrome is inherited in an autosomal recessive manner.
This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.
Parents of a proband
Parents of a proband are obligate heterozygotes for a disease-causing mutation and, therefore, carry one mutant allele.
Although systematic clinical studies have not been reported, heterozygotes do not appear to be at increased risk for any Werner syndrome-specific symptoms.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with Werner syndrome are obligate heterozygotes for a disease-causing mutation. Due to the very low prevalence in the US population, the risk of Werner syndrome in the offspring of an affected individual is negligible unless the affected individual and his/her reproductive partner are consanguineous. In Japan, where heterozygotes may be as common as 1/150, the risk for Werner syndrome in an offspring is still less than 1/500.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for WRN mutations using molecular genetic techniques is not offered because it is not clinically available.
Family planning. The optimal time for determination of genetic risk is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA. DNA banking is particularly important in situations in which molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.
No laboratories offering molecular genetic testing for prenatal diagnosis of Werner syndrome caused by WRN mutations are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering custom prenatal testing, see
.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| WRN | 8p12-p11.2 | Werner syndrome ATP-dependent helicase |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| WRN | WRN | 7486 (MIM No. 604611) | WRN |
For a description of the genomic databases listed, click here.
The mechanism by which WRN mutations cause the Werner syndrome phenotype is not clear. The WRN gene encodes a multifunctional nuclear protein of 1,432 amino acids [Yu et al 1996] that is a member of the RecQ family of DNA helicases. The N-terminal region of the protein encoded by WRN has exonuclease activity as well.
DNA-type helicases are ATP-dependent 3'- 5' helicases, which are needed to maintain genomic integrity in cells. Other human RecQ helicases include RecQL1, BLM (responsible for the Bloom syndrome), RecQL4 (responsible for the Rothmund-Thomson syndrome) and RecQ5 [Furuichi 2001, Ozgenc & Loeb 2005, Hisama et al 2006].
The WRN helicase preferentially unwinds DNA structures, such as tetraplex DNA, double-strand DNA with mismatch "bubbles" and Holliday junctions. It unwinds DNA-DNA double strands as well as DNA-RNA double strands. WRN exonuclease also preferentially digests single strands in complex DNA structures, such as double-stranded DNA with mismatched ends or bubbles [Brosh et al 2006]. WRN helicase and exonuclease activities are modified by binding to interacting proteins (e.g., Ku complex, p53, replication protein A) and by phosophorylation [Lee et al 2005].
Biochemical and cell biological studies suggest that WRN protein is involved in DNA repair, recombination, replication, and transcription as well as combined functions such as DNA repair during replication. WRN protein can potentially unwind or digest aberrant DNA structures accidentally generated during various DNA metabolisms and also regulate DNA recombination and repair processes by unwinding or digesting intermediate DNA structures. These findings are consistent with the notion that WRN plays a role in maintenance of genomic stability [Ozgenc & Loeb 2005, Hisama et al 2006].
Normal allelic variants: The WRN gene consists of 35 exons.
Pathologic allelic variants: Approximately 50 different disease-causing WRN mutations have been identified. All but one result from either stop codons, insertions, or deletions that result in a frame shift, or splicing donor or acceptor site mutations, which cause an exon to be skipped, resulting in a frame shift. A homozygous double amino acid substitution that results in an unstable protein has been identified in a German individual [Huang et al 2006]. The most common pathologic variant is 1336C>T, which accounts for 20%-25% of mutations in the Caucasian and Japanese populations [Huang et al 2006, Uhrhammer et al 2006]. A founder effect in the Japanese population is seen with the IVS 25-1G>C allele, which accounts for approximately 60% of mutations in this group [Satoh et al 1999].
Normal gene product: The normal gene product has 1,432 amino acids. At least six polymorphic variants have so far been described at the amino acid level [Castro et al 1999, Passarino et al 2001, Kamath-Loeb et al 2004]. The central region of the WRN protein contains the consensus domains of RecQ type helicases [Gray et al 1997] and the N-terminal region contains exonuclease domains [Huang et al 1998]. A nuclear localization signal is at the C-terminal end of the protein [Matsumoto et al 1997]. A highly acidic transactivation sequence is present between exonuclease and helicase domains [Balajee et al 1999]. There are two consensus domains in the C-terminal region whose functions have not been completely elucidated: a RecQ C-terminal conserved (RCQ) region and a helicase RNaseD C-terminal (HDRC) conserved region [Morozov et al 1997]. The RCQ region contains a zinc finger motif and a winged helix motif (WH). The zinc finger motif may be involved in the regulation of helicase enzymatic activity by modulating DNA binding as well as protein folding of WRN helicase. The DNA- and protein-binding domain (DPBD), which covers the WH motif, may play a role in directing the WRN protein to the site of action [Hu et al 2005]. The HDRC region is speculated to be involved in protein-DNA interactions.
There are two common polymorphisms for which there is some evidence for a role in the alteration of risks of certain age-related disorders in humans. Phe homozygosity at amino acid 1074 may be associated with reduced longevity and an age-dependent risk of atherosclerosis when compared to the common wild-type allele, Leu [Castro et al 2000]. In one study, Arg at amino acid 1367 was associated with a decreased risk of myocardial infarction compared to the wild-type protein, Cys [Ye et al 1997]; this conclusion has not yet been confirmed. A rare polymorphism, p.Arg834Cys, abolishes exonuclease activity. The effect on the phenotype is unknown [Kamath-Loeb et al 2004].
Cancers obtained from the normal individuals commonly showed alteration of the methylation status of the WRN gene promoter that results in the silencing of the WRN gene expression [Agrelo et al 2006].
Abnormal gene product: In addition to the loss of the nuclear localization signal in WRN mutations [Huang et al 2006], the mutant mRNAs and the resulting mutant proteins exhibit shorter half-lives than do the wild-type mRNA and WRNp [Yamabe et al 1997].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Werner syndrome
NCBI Genes and Disease
Werner syndrome
International Registry of Werner Syndrome
International Registry of Werner Syndrome
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
International Registry of Werner Syndrome
Phone: 206-543-5088
Fax: 206-685-6356
Web site
8 March 2007 (me) Comprehensive update posted to live Web site
13 January 2005 (me) Comprehensive update posted to live Web site
16 March 2004 (nh) Revision: Normal allelic variants
2 December 2002 (me) Review posted to live Web site
30 July 2002 (nh) Original submission
