Alternative titles; symbols
HGNC Approved Gene Symbol: WRN
SNOMEDCT: 51626007;
Cytogenetic location: 8p12 Genomic coordinates (GRCh38) : 8:31,033,810-31,176,138 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p12 | Werner syndrome | 277700 | Autosomal recessive | 3 |
Yu et al. (1996) identified the WRN gene by positional cloning. The predicted protein is 1,432 amino acids long and shows significant similarity to DNA helicases.
Imamura et al. (1997) cloned the mouse homolog of the human WRN gene.
Hu et al. (2005) stated that WRN has an N-terminal nuclease domain, followed by a helicase domain, a RecQ carboxy (RQC) domain, a helicase and ribonuclease D C-terminal (HRDC) domain, and a C-terminal nuclear localization signal (NLS). The RQC domain contains a 144-amino acid DNA- and protein-binding domain (DPBD) that also functions as a nucleolar targeting sequence. Using nuclear magnetic resonance spectroscopy, Hu et al. (2005) determined that DPBD consists of a winged helix (WH)-like motif and an unstructured C-terminal sequence of about 20 amino acids. They proposed that the WH motif binds to both DNA and proteins and that DPBD may regulate the enzymatic activity of WRN and its cellular localization through protein-protein interactions.
Liu and Johnson (2002) detected expression of WRN mRNA in all 24 human tissues tested, suggesting that it may be a housekeeping gene.
In their Table I, Lindor et al. (2000) provided a comparison of the 5 human RECQ helicases identified to that time. The RECQL3 gene, also called BLM (604610), is deficient in Bloom syndrome (210900). The RECQL2 gene, also known as WRN, is deficient in Werner syndrome (277700), and the RECQL4 gene (603780) is deficient in Rothmund-Thomson syndrome (268400). No disorder had been related to RECQL (RECQ1; 600537) or RECQL5 (603781).
Matsumoto et al. (1997) defined the genomic structure of the WRN gene and determined intron-exon boundaries for 35 exons, each 68 to 767 bp. The region most highly homologous to RecQ-type helicases was contained in exons 14 through 21. Yu et al. (1997) determined the intron-exon structure of the WRN gene. A total of 35 exons were defined, with the coding sequence beginning in the second exon.
Liu and Johnson (2002) stated that the WRN promoter does not contain either a TATA or a CAAT motif, but does contain 2 Sp1 elements and 1 RCE motif that are required for promoter activity. The authors also reviewed previous research demonstrating that WRN transcription can start from multiple sites.
Yu et al. (1996) identified the WRN gene within the Werner syndrome critical region on 8p12-p11.2.
Imamura et al. (1997) assigned the mouse homolog of the human WRN gene to 8A4 by fluorescence in situ hybridization.
Gray et al. (1997) pointed out that the homology of the WRN protein to members of the RecQ family of DNA helicases does not necessarily mean that the WRN gene encodes an active helicase. For example, the Saccharomyces cerevisiae RAD26 gene protein and the human transcription-repair coupling factor mutant in Cockayne syndrome B (609413) are highly homologous to known helicases, yet neither encodes an active helicase. Gray et al. (1997) reported work indicating that the Werner syndrome protein does indeed catalyze DNA unwinding.
Matsumoto et al. (1997) presented evidence that the helicase that is defective in Werner syndrome is missing the NLS and that this leads to impaired nuclear import as a major contributing factor in the molecular pathology of the disorder. The finding helped to explain the enigma that most Werner syndrome patients have similar clinical phenotypes no matter how different their mutations. The role the Werner syndrome helicase plays in the nucleus in preventing premature aging remained to be clarified.
To define better the function of WRN protein, Marciniak et al. (1998) determined its subcellular localization. By indirect immunofluorescence, using polyclonal anti-human WRN, they showed a predominant nucleolar localization. Studies of WRN mutant cell lines confirmed the specificity of antibody recognition. No difference was seen in the subcellular localization of the WRN protein in a variety of normal and transformed human cell lines, including both carcinomas and sarcomas. The nucleolar localization of human WRN protein was supported by the finding that upon biochemical subcellular fractionation, WRN protein was present in an increased concentration in a subnuclear fraction enriched for nucleolar proteins. Marciniak et al. (1998) also determined the subcellular localization of the mouse WRN homolog. In contrast to human WRN protein, mouse WRN protein was present diffusely throughout the nucleus.
The yeast sgs1 gene encodes a DNA helicase with similarity to the WRN and Bloom syndrome genes. Sinclair et al. (1997) showed that mutation of sgs1 causes premature aging in yeast mother cells as demonstrated by shortened life span and the aging-induced phenotypes of sterility and redistribution of the Sir3 silencing protein from telomeres to the nucleolus. Furthermore, in old sgs1 cells the nucleolus was enlarged and fragmented, changes that also occur in old wildtype cells. Their findings suggested a conserved mechanism of cellular aging that may be related to nucleolar structure. The similar effect of the related sgs1 and WRN genes on yeast and human aging, along with age-associated changes in rDNA content reported for several mammalian species, suggested that a common mechanism may underlie aging in eukaryotes.
Sinclair and Guarente (1997) found that mutants for sgs1 accumulate extrachromosomal rDNA circles (ERCs) more rapidly than cells with wildtype sgs1 leading to premature aging and a shorter life span. These ERCs are nucleic acid circles that excise from the yeast rDNA locus and replicate via the autonomously replicating sequence present in each rDNA repeat.
Bloom syndrome, which has features quite different from those of Werner syndrome, is caused by defects in another human RecQ-like helicase, RECQL3. Both Werner syndrome and Bloom syndrome show an increased rate of chromosomal aberration. Yamagata et al. (1998) showed that yeast sgs1 helicase acts as a suppressor of illegitimate recombination through homologous recombination and that human BLM and WRN helicases can suppress the increased homologous and illegitimate recombinations in the S. cerevisiae sgs1 mutant. The results implied a role of BLM and WRN helicases in the control of genomic stability in human cells. Similar to sgs1 helicase, BLM helicase suppressed the cell growth in the top3 sgs1 mutation background and restored the increased sensitivity of the sgs1 mutant to hydroxyurea, but the WRN helicase did not. Thus, BLM and WRN helicases may have different roles in human cells.
DNA helicases are involved in many aspects of DNA metabolism, including transcription, replication, recombination, and repair. In the yeast Saccharomyces cerevisiae, the absence of the Sgs1 helicase results in genomic instability and accelerated aging. In human cells, mutations in orthologs of SGS1 lead not only to Werner syndrome but also to Bloom syndrome or Rothmund-Thomson syndrome. All 3 are rare, autosomal recessive disorders characterized by genetic instability associated with cancer predisposition. Gangloff et al. (2000) showed that Sgs1 deletion mutants are deficient in DNA repair and are defective for induced recombination events that involve homologous chromosomes. The role of homologous recombination is further evidenced in haploid cells in which both Sgs1 and Srs2 proteins are absent. Yeast Srs2 encodes another DNA helicase involved in the maintenance of genomic stability. Gangloff et al. (2000) interpreted their data as indicating that some defects observed in Werner, Bloom, and Rothmund-Thomson syndromes are the consequence of unrestrained recombination.
The initiation of DNA replication involves a minimum of 4 factors: a specific DNA sequence (origin), an initiator protein that binds to the origin, a helicase that unwinds the origin, and a protein that binds single-stranded DNA and stabilizes the unwound origin. In eukaryotic cells, the origin recognition complex (ORC) is the initiator protein, and replication protein A (RPA1; 179835) is the single-stranded DNA-binding protein. However, the helicase had not been identified and the nature of origins remained elusive, except in the case of S. cerevisiae. A unique feature of eukaryotic DNA replication is that it occurs at a few hundred discrete foci. Thus, it has been proposed that a real origin must contain a specific DNA sequence and must be attached to replication foci. Using Xenopus laevis egg extracts, Yan and Newport (1995) identified and purified a 170-kD protein, called focus-forming activity 1 (FFA1), that is required for the formation of replication foci. Yan et al. (1998) reported that FFA1 has DNA-helicase activity. Moreover, it is a homolog of the human Werner syndrome gene product WRN, a protein associated with premature aging in humans.
Ketting et al. (1999) identified the mut7 gene in C. elegans, which is homologous to the human WRN gene. The mut7 C. elegans protein is implicated in the silencing mechanism of transposons and the phenomenon of RNA interference.
Huang et al. (1998) demonstrated that the wildtype WRN protein is a 3-prime-to-5-prime exonuclease. Genetic evidence for WRN exonuclease activity was obtained by introducing point mutations at critical amino acids in the exonuclease domain (D82A and E84A). These mutants retained the wildtype level of helicase activity, but had little or no 3-prime-to-5-prime exonuclease activity. The lys577-to-met mutant (K577M; 604611.0009), in contrast, was devoid of helicase activity, but had 3-prime-to-5-prime exonuclease activity comparable to that of wildtype WRN. Thus, the exonuclease activity resides in the N terminus and is physically and functionally separable from the helicase activity. The identification of an exonuclease activity in WRN clearly distinguishes it from other human RecQ-like helicases, and may help explain the differences of phenotype between Werner syndrome and Bloom syndrome.
Wyllie et al. (2000) showed that forced expression of telomerase (187270) in Werner syndrome fibroblasts confers extended cellular life span and probable immortality. Telomerase activity and telomere extension is sufficient to prevent premature senescence of Werner syndrome fibroblast cultures. The findings suggested that one consequence of the Werner syndrome defect is an acceleration of normal telomere-driven replicative senescence, and suggested a route to therapeutic intervention in this human progeroid syndrome.
Von Kobbe et al. (2002) confirmed interaction between BLM (604610) and WRN in immunoprecipitates of soluble nuclear extracts of HeLa cells. Immunolocalization of endogenous BLM and transfected WRN in several human cell lines indicated colocalization in some nuclear foci and not in others, suggesting that the interaction between these proteins is dynamic. Using pull-down assays with several truncation mutants, von Kobbe et al. (2002) determined that the BLM-binding regions of WRN include the N-terminal exonuclease domain and the RQC-containing regions. They mapped the WRN-binding region of BLM to the middle of the molecule. Von Kobbe et al. (2002) showed that BLM, through binding the exonuclease domain, inhibited WRN exonuclease activity. There was no effect of BLM on WRN helicase activity.
Kamath-Loeb et al. (2000) showed that WRN functionally interacts with DNA polymerase delta, the major DNA polymerase required for chromosomal DNA replication and repair. Their findings suggested that WRN may facilitate POLD-mediated DNA replication and/or DNA repair and that disruption of the interaction in Werner syndrome cells may contribute to the previously observed S-phase defects and/or the unusual sensitivity to a limited number of DNA damaging agents. The helicase and exonuclease activities of the Werner protein suggest that it functions in DNA transactions. Szekely et al. (2000) presented several lines of evidence that WRN interacts specifically with the p50 subunit of polymerase delta (POLD2; 600815). The results suggested that one of the functions of WRN protein is to modify directly DNA replication via its interaction with p50 and abet dynamic relocalization of the DNA polymerase delta complexes within the nucleus.
By chromatographing HeLa nuclear extracts to identify proteins that bind to the C terminus of WRN, Cooper et al. (2000) detected WRN interacting with Ku70 (G22P1; 152690) and Ku86, even in the absence of DNA. The Ku complex had no effect on WRN helicase or ATPase activities but did stimulate WRN exonuclease activity, which occurs at the N terminus. The authors proposed that since cells deficient in WRN, Ku70, or Ku86 undergo premature replicative senescence and have elevated levels of chromosomal abnormalities, defective exonuclease function could lead to the aging phenotype.
Opresko et al. (2002) found that WRN colocalized and physically interacted with the critical telomere maintenance protein TRF2 (602027) and that the interaction was mediated by the RecQ conserved C-terminal region of WRN. In vitro, TRF2 showed high affinity for WRN and for BLM, and TRF2 interaction with either helicase resulted in stimulation of its activity. WRN or BLM, partnered with replication protein A (see 179835), actively unwound long telomeric duplex regions that were pre-bound by TRF2. Opresko et al. (2002) concluded that TRF2 functions with WRN, and possibly BLM, in a common pathway at the telomeric ends.
Franchitto and Pichierri (2002) reviewed the roles of RECQL2 and RECQL3 in resolution of a stall in DNA replication, as well as their possible interaction with the MRE11 (600814)-RAD50 (604040)-NBS1 (602667) complex. Components of this complex are mutated in 2 genetic instability syndromes, Nijmegen breakage syndrome (251260) and ataxia telangiectasia-like disorder (604391).
Bai and Murnane (2003) investigated how a WRN protein containing the dominant-negative K577M mutation (604611.0009) influences the stability of telomeres in a human tumor cell line expressing telomerase. The results demonstrated an increased rate of telomere loss and chromosome fusion in cells expressing the mutant. Expression of the mutant resulted in reduced levels of telomerase activity; however, the absence of detectable changes in average telomere length demonstrated that WRN-associated telomere loss results from stochastic events involving complete telomere loss or loss of telomere capping function. Thus, telomere loss can contribute to chromosome instability in cells deficient in the WRN gene regardless of the expression of telomerase activity.
Crabbe et al. (2004) demonstrated that cells lacking WRN exhibit deletion of telomeres from single sister chromatids. Only telomeres replicated by lagging strand synthesis were affected, and prevention of loss of individual telomeres was dependent on the helicase activity of WRN. Telomere loss could be counteracted by telomerase activity. Crabbe et al. (2004) proposed that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing telomere dysfunction and consequent genomic instability.
To investigate the role of WRN in replication, Sharma et al. (2004) examined the ability of WRN to rescue cellular phenotypes of a yeast dna2 mutant defective in a helicase-endonuclease that participates with flap endonuclease-1 (FEN1; 600393) in Okazaki fragment processing. Complementation studies indicated that a conserved noncatalytic C-terminal domain of human WRN rescued dna2-1 mutant phenotypes of growth, cell cycle arrest, and sensitivity to the replication inhibitor hydroxyurea or DNA-damaging agent methylmethane sulfonate. Physical interactions between WRN and yeast FEN1 were demonstrated by coimmunoprecipitation, affinity pull-down experiments, and by ELISA assays with purified recombinant proteins. Biochemical analyses demonstrated that the C-terminal domain of WRN or BLM (604610) stimulated FEN1 cleavage of its proposed physiologic substrates during replication. Sharma et al. (2004) suggested that the WRN/FEN1 interaction is biologically important in DNA metabolism and supported a role of the conserved noncatalytic domain of a human RecQ helicase in DNA replication intermediate processing.
Deschenes et al. (2005) examined the expression profile of mouse embryonic cells lacking both Recql2 and Parp1 (173870), which is also involved in DNA repair, using microarray and RT-PCR analysis. All mutant cells exhibited altered expression of genes normally responding to oxidative stress. More than 50% of misregulated genes identified in double-mutant mouse cells were not altered in mouse cells with either the Recql2 or Parp1 mutation alone. The impact on gene expression profile when both Recql2 and Parp1 were mutated was greater than a simple addition of individual mutant genotype. In addition, double-mutant cultured mouse cells showed major misregulation of genes involved in apoptosis, cell cycle control, embryonic development, metabolism, and signal transduction.
Agrelo et al. (2006) reported that WRN function was abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. Restoration of WRN expression induced tumor suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening 630 human primary tumors from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis.
Kamath-Loeb et al. (2007) presented in vitro and in vivo data demonstrating functional interaction between WRN and the translesion polymerases POLH (603968), POLK (605650), and POLI (605252). In vitro, WRN stimulated the extension activity of translesion polymerases on lesion-free and lesion-containing DNA templates, and it alleviated pausing at stalling lesions. Stimulation was mediated through an increase in the apparent V(max) of the polymerization reaction. By accelerating the rate of nucleotide incorporation, WRN increased mutagenesis by POLH. In vivo, WRN and POLH colocalized at replication-dependent foci in response to ultraviolet C irradiation.
Michishita et al. (2008) showed that the human SIRT6 protein (606211) is an NAD(+)-dependent histone H3 lysine-9 (H3K9) deacetylase that modulates telomeric chromatin. They showed that SIRT6 associates specifically with telomeres, and SIRT6 depletion led to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibited abnormal telomere structures that resemble defects observed in Werner syndrome. At telomeric chromatin, SIRT6 deacetylated H3K9 and was required for the stable association of RECQL2, the factor that is mutated in Werner syndrome. Michishita et al. (2008) proposed that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. The authors concluded that their findings constituted the first identification of a physiologic enzymatic activity of SIRT6, and linked chromatin regulation by SIRT6 to telomere maintenance and to a human premature aging syndrome.
Mimitou and Symington (2008) demonstrated that yeast Exo1 nuclease (606063) and Sgs1 helicase functioned in alternative pathways for double-strand break (DSB) processing. Novel, partially resected intermediates, whose initial generation depended on Sae2 (see 604124), accumulated in yeast lacking both Exo1 and Sgs1 and were poor substrates for homologous recombination. When Sae2 was absent, in addition to Exo1 and Sgs1, homology-dependent repair failed and unprocessed DSBs accumulated. Mimitou and Symington (2008) concluded that there is a 2-step mechanism for DSB processing during homologous recombination, with the Mre11 complex and Sae2 removing a small oligonucleotide from DNA ends to form an early intermediate, followed by processing of this intermediate by Exo1 and/or Sgs1 to generate extensive tracts of single-stranded DNA that serve as a substrate for Rad51 (179617).
Zhang et al. (2015) generated a human Werner syndrome model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulated features of premature cellular aging, a global loss of histone H3 trimethylated on lys9 (H3K9me3), and changes in heterochromatin architecture. Zhang et al. (2015) showed that WRN associates with heterochromatin proteins SUV39H1 (300254) and HP1-alpha (CBX5; 604478) as well as with nuclear lamina-heterochromatin-anchoring protein LAP2-beta (see 188380). Targeted knockin of catalytically inactive SUV39H1 in wildtype MSCs recapitulated accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decreases in WRN and heterochromatin marks were detected in MSCs from older individuals. Zhang et al. (2015) concluded that their observations uncovered a role for WRN in maintaining heterochromatin stability and highlighted heterochromatin disorganization as a potential determinant of human aging.
Chan et al. (2019) hypothesized that DNA repair defects would give rise to synthetic lethal relationships and queried dependencies in cancers with microsatellite instability, which results from deficient DNA mismatch repair. Chan et al. (2019) analyzed data from large-scale silencing screens using CRISPR-Cas9-mediated knockout and RNA interference, and found that the RecQ DNA helicase WRN was selectively essential in microsatellite instability models in vitro and in vivo, yet dispensable in models of cancers that are microsatellite-stable. Depletion of WRN induced double-stranded DNA breaks and promoted apoptosis and cell cycle arrest selectively in microsatellite instability models. Microsatellite instability cancer models required the helicase activity of WRN, but not its exonuclease activity. Chan et al. (2019) concluded that WRN is a synthetic lethal vulnerability and a drug target for microsatellite instability cancers.
Van Wietmarschen et al. (2020) showed that TA-dinucleotide repeats are highly unstable in microsatellite instability (MSI) cells and undergo large-scale expansions, distinct from previously described insertion or deletion mutations of a few nucleotides. Expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and require unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 (606591) nuclease, leading to massive chromosome shattering. Van Wietmarschen et al. (2020) concluded that their findings identified a distinct biomarker that underlies the synthetic lethal dependence on WRN.
Yu et al. (1996) identified 4 mutations in the WRN gene in patients with Werner syndrome (WRN; 277700). Two of the mutations (604611.0003 and 604611.0004) were reportedly splice junction mutations with the predicted result being the exclusion of exons from the final messenger RNA. One of these mutations (604611.0004), which resulted in a frameshift and a predicted truncated protein, was found in the homozygous state in 60% of Japanese Werner syndrome patients examined. The other 2 mutations were nonsense mutations (604611.0001 and 604611.0002). The identification of a mutated putative helicase as the gene product of the WRN gene suggested to Yu et al. (1996) that defective DNA metabolism is involved in a complex process of aging in Werner syndrome patients.
Oshima et al. (1996) reported 9 new WRN mutations in 10 Werner syndrome patients, including 4 Japanese patients and 6 Caucasian patients. These mutations were located at different sites across the coding region. Oshima et al. (1996) noted that all of the WRN mutations found to date either create a stop codon or cause frameshifts that lead to premature terminations. They noted that the WRN protein is partially homologous to RecQ helicases and that it contains 7 helicase motifs, 2 of which have been found in all ATP-binding proteins. Oshima et al. (1996) briefly reviewed the functions of helicases and reported that DNA helicases have been implicated in a number of molecular processes, including unwinding of DNA during replication, DNA repair, and accurate chromosomal segregation.
Goto et al. (1997) studied the helicase gene mutations previously described by Yu et al. (1996) in 89 Japanese Werner syndrome patients. Thirty-five (39.3%) were homozygous for mutation 4 (604611.0004); 1 (1.1%) was homozygous for mutation 1 (604611.0001); 6 (6.7%) were positive for both mutations 1 and 4; 1 was homozygous for a new mutation, which they designated mutation 5 (604611.0005); 13 (14.6%) had a single copy of mutation 4; 3 (3.4%) had a single copy of mutation 1; and the remaining 30 (33.8%) were negative for all 5 mutations. Of the 178 chromosomes in the 89 patients, 89 (50%) carried mutation 4, 11 (6.2%) carried mutation 1, and 2 (1.1%) carried mutation 5. In 76 chromosomes (42.7%), no mutation was identified.
Yu et al. (1997) screened Werner syndrome patients for mutations in the WRN gene and identified 5 new ones. Four of the new mutations either partially disrupted the helicase domain region or resulted in predicted protein products lacking the entire helicase region. Their results confirmed that mutations in the WRN gene are responsible for Werner syndrome. In addition, the location of the mutations indicated that the presence or absence of the helicase domain does not influence the Werner syndrome phenotype, suggesting that this syndrome is the result of complete loss of function of the WRN gene product.
Moser et al. (1999) reviewed the spectrum of WRN mutations in Werner syndrome, the organization and potential functions of the WRN protein, and the possible mechanisms linking the loss of WRN function with the clinical and cellular phenotypes of Werner syndrome.
Monnat (1999) cited results from his own laboratory and from that of the AGENE Research Institute indicating that 80% of the WRN mutations in Japanese Werner syndrome patients led to a lack of detectable mutant protein. Thus many and perhaps all Werner syndrome-associated WRN mutations are likely to be functionally equivalent null alleles. These results contradict the suggestion of Ishikawa et al. (1999) that a different spectrum of mutations in the WRN gene in Japanese may confer a higher risk of thyroid carcinoma of the papillary or follicular type. However, the consistent absence of WRN protein in the cells of patients with Werner syndrome could both favor and partially explain the development of thyroid carcinoma with follicular and anaplastic, as opposed to the more papillary, histology.
Huang et al. (2006) summarized the spectrum of 50 distinct mutations that had been discovered in 99 Werner syndrome patients by the International Register of Werner Syndrome and by others in the decade since the first cloning of the WRN gene in 1996; 25 of these had not previously been published. All WRN mutations previously reported had 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. Huang et al. (2006) reported 2 new mutations in the N terminus that resulted in instability of the WRN protein. Clinical data confirmed 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 to 48 years, was found to be 54 years.
Lebel and Leder (1998) deleted a segment of the mouse Wrn gene that encodes 21 amino acids within the helicase domain. Homozygous mutant mice were born at reduced mendelian ratios, but surviving homozygotes appeared to grow normally. One of the 2 male homozygotes necropsied at 10 months of age displayed extensive myocardial fibrosis not seen in controls or heterozygous littermates. The oldest homozygous female (13.5 months) developed a T-cell lymphoma not seen in controls or heterozygous littermates. Although several DNA repair systems appeared intact in homozygous mutant embryonic stem cells, such cells displayed a higher mutation rate and were significantly more sensitive to topoisomerase inhibitors than wildtype embryonic stem cells. Fibroblasts derived from homozygous Wrn -/- embryos showed premature loss of proliferative capacity. At the molecular level, wildtype, but not mutant, Wrn protein copurified with a multiprotein DNA replication complex.
That enforced telomerase expression can rescue premature senescence of cultured cells from individuals with Werner syndrome (Wyllie et al., 2000), and the lack of disease phenotype in Wrn-deficient mice with long telomeres (Lombard et al., 2000), implicated telomere attrition in the pathogenesis of Werner syndrome. Chang et al. (2004) showed that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (602322), which encodes the telomerase RNA component, telomere dysfunction elicited a classic Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes (125853), and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicated that the delayed manifestation of the complex pleiotropy of Wrn deficiency is related to telomerase shortening.
Deschenes et al. (2005) generated double-mutant mice lacking both Recql2 and Parp1. Double-mutant mouse embryos showed increased apoptosis and developmental defects with decreased survival in utero. Surviving adult double-mutant mice exhibited high levels of reactive oxygen species (ROS) and DNA oxidative damage and increased intracellular protein phosphorylation in heart and liver compared to wildtype.
In 4 of 5 Japanese patients with Werner syndrome (WRN; 277700) studied, Yu et al. (1996) found a change in codon 1305 of the WRN gene from CGA (arg) to TGA (stop) (R1305X). All the Japanese patients were offspring of first-cousin marriages; the same mutation was found in a Caucasian from a second-cousin marriage. All patients were homozygous.
In a Japanese patient with Werner syndrome (WRN; 277700) whose parents were first cousins, Yu et al. (1996) found homozygosity for a change of codon 1165 of the WRN gene from CAG (gln) to TAG (stop) (Q1165X).
In 3 sibs with Werner syndrome (WRN; 277700) in a Syrian family, Yu et al. (1996) found a homozygous 4-bp deletion spanning a splice junction in the WRN gene, predicting a frameshift and premature stop codon at residue 1393. A fourth sib, aged 21 years, was homozygous for the same mutation but was too young for a definitive diagnosis of Werner syndrome. Although these individuals were not from a consanguineous marriage, they did share the same haplotype across the WRN region.
Oshima et al. (1996) found that this 4-bp deletion (ACAG) occurred at the beginning of the exon, rather than at the splice junction site, and resulted in a termination at nucleotides 3971-3973 (TAG).
In a Japanese patient, born of first-cousin parents, with Werner syndrome (WRN; 277700), Yu et al. (1996) detected a homozygous G-to-C transversion in the WRN gene that changed a splice donor sequence from ApG to ApC, resulting in a frameshift of codons 1078 to 1092. Individuals with Werner syndrome from 18 of 30 Japanese kindreds were found to be homozygous for this mutation; 60% of Japanese patients carried this mutation. Among mutation carriers, 12 of 16 had a 141-bp allele at a glutathione reductase (GSR2, D8S540) short-tandem repeat polymorphism (STRP), which is overrepresented in Werner syndrome patients (frequency = 0.40) and relatively rare in Japanese controls (frequency = 0.07) (Yu et al., 1994). This mutation was not observed by Yu et al. (1996) in 48 Caucasian Werner syndrome patients. Among 187 Japanese control individuals, 1 heterozygote was observed for an estimated gene frequency of 0.003, which is comparable with gene frequency estimates (0.001 to 0.005) in Japanese based on Werner syndrome prevalence rates and consanguinity estimates. In this mutation, the exon preceding the mutated splice donor sequence was missing. The premature stop codon resulting from frameshift occurred in the following exon and resulted in a predicted 1060-amino acid truncated protein.
Matsumoto et al. (1997) showed that almost all the patients homozygous for this mutation, which the authors called mutation 4, shared a rare haplotype that was observed across 19 loci, extending a distance of more than 1.4 Mb across the WRN gene, consistent with the view that the loci derived from a single Japanese ancestor. This mutation (50.8%) and mutation 6 (R368X; 604611.0006; 17.5%) accounted for approximately 70% of all mutations in 63 independent families studied.
Huang et al. (2006) indicated that this mutation, designated 3139-1G-C, was the second most frequent mutation in their international registry, occurring in 22 Japanese subjects and accounting for 67% of Japanese WRN cases among their registry cases. This mutation was seen exclusively in Japanese WRN patients. It resulted in deletion of exon 26 and truncation of the protein immediately after the RQC domain.
In a Japanese patient with Werner syndrome (WRN; 277700), Goto et al. (1997) identified homozygosity for an insertion of an A at nucleotide 4146 of the WRN gene. The A was inserted in the sequence of GCGAGC to give rise to GCGAAGC, resulting in a translational frameshift and generation of a stop codon 38 bp downstream. This patient had a unusual type of osteosarcoma.
In 1 Caucasian and 3 Japanese patients with Werner syndrome (WRN; 277700), Oshima et al. (1996) identified a 1336C-T transition in the WRN gene, resulting in an arg368-to-ter (R368X) substitution and a truncated protein lacking helicase function. Matsumoto et al. (1997) found that most Japanese patients homozygous for this mutation in exon 9 of WRN, which the authors called mutation 6, share a rare haplotype, similar to the haplotype associated with another mutation (mutation 4; 604611.0004). These results suggested that these 2 mutations arose independently in almost identical rare haplotypes. This mutation (17.5%) and mutation 4 (50.8%) accounted for approximately 70% of all mutations in 63 independent families studied.
In an Austrian family with Werner syndrome (WRN; 277700), Meisslitzer et al. (1997) described compound heterozygosity of the WRN gene for WRN mutations in 2 brothers with typical Werner syndrome. At the age of 35 and 26 years, they were of short stature (165 cm and 157 cm, respectively) with bird-like face, hypermelanosis, early cataracts, atrophic skin, diabetes mellitus, and osteoporosis. In both, hyaluronate excretion in the urine was markedly elevated. The diagnosis was confirmed by cellular parameters such as chromosomal instability, population doubling time, and life span of fibroblasts. The older brother had been married and had had 2 children. He died at the age of 37 from myocardial infarction, acute leukemia, and pneumonia. A third brother, the oldest child in the sibship, seemed to be similarly affected, but refused further examination. One allele of the WRN gene showed an A-to-T transversion at an exon-intron boundary at the highly conserved 5-prime CpA sequence of the intron 31 splice donor site. The mutation predicts a deletion of the 113-bp exon preceding the 5-prime end of the intron, with frameshift resulting in a termination signal (TGA) at nucleotide 3816. The father and a healthy brother were also heterozygous for this splice mutation. The protein produced by this allele is 275 amino acids shorter than the normal one.
In the second allele of the WRN gene in 2 Austrian brothers with Werner syndrome (WRN; 277700) studied by Meisslitzer et al. (1997), a mutation in a more 5-prime position than that described for the other allele (604611.0007) was expected because of the early onset of hypermelanosis and growth retardation (around 13 years), and cataract (operations at 23 and 25 years of age). Indeed, a second mutation was identified as a 1-bp deletion at nucleotide 1396. This led to a frameshift with a new stop codon at nucleotide 1406-1408, resulting in a protein of 391 amino acids.
Wang et al. (2000) demonstrated that the lys577-to-met (K577M) mutation in the WRN gene functions in vivo as a dominant negative. Bai and Murnane (2003) studied telomere instability in a human tumor cell line expressing a WRN protein containing the K577M mutation.
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