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Clinical diagnostic criteria for Werner syndrome Major signs and symptoms (onset over 10 years old) Cataracts (bilateral)
Source publication
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. Indi...
Similar publications
Werner syndrome is an autosomal recessive disease of premature aging caused by a polymorphic C1367T mutation in the Werner (WRN) gene. Although there are differences between the pathobiology of normal aging and the phenotype of Werner syndrome, the clinical age-related changes are similar. The aim of the study was to investigate the incidence of th...
Objective:
RECQL4 (a member of the RECQ helicase family) upregulation has been reported to be associated with tumor progression in several malignancies. However, whether RECQL4 sustains esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we determined the functional role for RECQL4 in ESCC progression.
Methods:
RECQ...
One of the causes of ageing is thought to be the accumulation of senescent cells.
Since normal ageing is very complex, diseases with single gene mutations
(progeroid syndromes) which show many features of normal ageing have been
used as models in ageing research. Werner's syndrome is the progeroid syndrome
which mimics most of the features of norma...
In budding yeast, an HO endonuclease-inducible double-strand break (DSB) is efficiently repaired by several homologous recombination (HR) pathways. In contrast to gene conversion (GC), where both ends of the DSB can recombine with the same template, break-induced replication (BIR) occurs when only the centromere-proximal end of the DSB can locate h...
RECQ5 is one of five RecQ helicases found in humans and is thought to participate in homologous DNA recombination by acting as a negative regulator of the recombinase protein RAD51. Here, we use kinetic and single molecule imaging methods to monitor RECQ5 behavior on various nucleoprotein complexes. Our data demonstrate that RECQ5 can act as an ATP...
Citations
... Mutations in the WRN gene are associated with Werner syndrome [65,73]. It is a rare autosomal recessive disorder classified as one of the progeria syndromes, thus associated with premature ageing and increased risk for several malignancies, especially melanoma, meningioma, soft tissue sarcoma, leukemia, osteosarcoma, but also differentiated thyroid cancer, usually follicular carcinoma [65,73,95]. It may increase the cancer risk irrespective of their location. ...
The genome sequencing technologies reveal the molecular mechanisms of differentiated thyroid cancer (DTC). Unlike somatic mutation analysis from thyroidectomy samples, germline mutations showing genetic susceptibility to DTC are less understood. The study aimed to assess the prevalence of germline mutations predisposing to DTC in a cohort of Polish individuals based on their whole genome sequencing (WGS) data. We analyzed sequencing data from 1076 unrelated individuals, released openly for academic and clinical research as The Thousand Polish Genomes database (https://1000polishgenomes.com). The list of genes chosen for further analysis was based on the review of previous studies. The cohort contained 104 variants located within the coding and noncoding DNA sequences of 90 genes selected by ClinVar classification as pathogenic and potentially pathogenic. The frequency of variants in the Polish cohort (our study) was compared to the frequency estimated for the non-Finnish European population, obtained from the gnomAD database (gnomad.broadinstitute.org). Statistically significant variants included 23 genes. Even though the Polish population is genetically similar to other European populations, there are significant differences in variant frequencies contributing to the disease development and progression, such as RET, CHECK2, BRCA1, SLC26A4 or TERT. Further studies are needed to identify genomic variants associated directly with DTC.
... SHH also plays an important role in finger patterning and regulates facial development and growth, as well as the differentiation of cranial neural crest cell-derived skeletal structures [60]. The group of diseases caused by SHH gene mutations includes congenital hand deformities; Werner's syndrome; Acheiropodia; and various forms of polydactyly and syndactyly such as Polydactyly type 1 (PPD1), Polydactyly type 2 (PPD2), and Syndactyly type 4 Haas type [61][62][63]. Laurin-Sandlow syndrome is a severe craniofacial and neurological syndrome, an autosomal-dominant disorder characterized by polysyndactyly of the hands and feet, mirror image duplication of the feet, and nasal defects caused by a heterozygous mutation in an SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene on chromosome 7q36 [64]. ...
The hedgehog (Hh) family consists of numerous signaling mediators that play important roles at various stages of development. Thus, the Hh pathway is essential for bone tissue development and tumorigenesis. Gorlin syndrome is a skeletal and tumorigenic disorder caused by gain-of-function mutations in Hh signaling. In this review, we first present the phenotype of Gorlin syndrome and the relationship between genotype and phenotype in bone and craniofacial tissues, including the causative gene as well as other Hh-related genes. Next, the importance of new diagnostic methods using next-generation sequencing and multiple gene panels will be discussed. We summarize Hh-related genetic disorders, including cilia disease, and the genetics of Hh-related bone diseases.
... On the other hand, in progeria Werner's syndrome, the ablation of the WNR gene may lead to the development of myeloid malignancies as result of competitive fitness by inactivating p53 [23]. Patients with Werner's syndrome are also characterized by a high predisposition to various cancer types and as well as ocular cataracts [23,24]. The increased incidence of ocular cataracts in patients with Werner's syndrome may be explained by the role of p53 in preventing cataracts and the existing relationship between WNR and p53. ...
Simple Summary
Ocular malignancies encompass a broad range of disorders that affect the eyelids, orbit, and eye and have significant impacts for national healthcare systems. Due to its exposure to various stressors, the eye is an anatomical site susceptible to cellular toxicity and tissue damage, which can result in significant vision loss. In this context, similar to other tissue types, p53 plays a crucial role in maintaining ocular homeostasis. However, few in vitro experimentation and clinical trials of p53 pathway modulators have been conducted. The aim of this review is to discuss the potential of pharmacological p53 activators as a novel targeted therapy for managing ocular tumors.
Abstract
The pivotal role of p53 in the regulation of a vast array of cellular functions has been the subject of extensive research. The biological activity of p53 is not strictly limited to cell cycle arrest but also includes the regulation of homeostasis, DNA repair, apoptosis, and senescence. Thus, mutations in the p53 gene with loss of function represent one of the major mechanisms for cancer development. As expected, due to its key role, p53 is expressed throughout the human body including the eye. Specifically, altered p53 signaling pathways have been implicated in the development of conjunctival and corneal tumors, retinoblastoma, uveal melanoma, and intraocular melanoma. As non-selective cancer chemotherapies as well as ionizing radiation can be associated with either poor efficacy or dose-limiting toxicities in the eye, reconstitution of the p53 signaling pathway currently represents an attractive target for cancer therapy. The present review discusses the role of p53 in the pathogenesis of these ocular tumors and outlines the various pharmacological activators of p53 that are currently under investigation for the treatment of ocular malignancies.
... Consistent with these observations, in vitro studies with primary mouse cortical neurons revealed that non-phosphorylated tau accumulates perinuclearly upon DSBs formation, followed by accumulation of phosphorylated tau immunoreactive to AT8 antibody (Asada-Utsugi et al., 2022). In the field of pathological ageing, deficiencies in the DNA repair machineries result in many PS such as Werner syndrome (Muftuoglu et al., 2008), Cockayne syndrome (Laugel, 2013) and xeroderma pigmentosum (Lehmann et al., 2011). The wealth of DNA repairdeficient models established for studying these progeroid syndromes offered an opportunity to explore neurodegeneration in a high DNA damage susceptibility system. ...
... Werner syndrome (WS) is a DNA repair-related premature ageing syndrome caused by mutations in a RecQ family DNA helicase, WRN (Muftuoglu et al., 2008). In contrast to progeroid laminopathies, Werner syndrome has a delayed onset-typically recognised by the third or fourth decades of life and is therefore sometimes TA B L E 3 Benefits and limitations of specific progeric models for tauopathy research. ...
Ageing is the greatest risk factor of late-onset neurodegenerative diseases. In the realm of sporadic tauopathies, modelling the process of biological ageing in experimental animals forms the foundation of searching for the molecular origin of pathogenic tau and developing potential therapeutic interventions. Although prior research into transgenic tau models offers valuable lessons for studying how tau mutations and overexpression can drive tau pathologies, the underlying mechanisms by which ageing leads to abnormal tau accumulation remains poorly understood. Mutations associated with human progeroid syndromes have been proposed to be able to mimic an aged environment in animal models. Here, we summarise recent attempts in modelling ageing in relation to tauopathies using animal models that carry mutations associated with human progeroid syndromes, or genetic elements unrelated to human progeroid syndromes, or have exceptional natural lifespans, or a remarkable resistance to ageing-related disorders.
... Werner syndrome (WS) is a premature aging disease characterized by early onset of age-related phenotypes, such as greying hair, hair loss, cataracts, premature arteriosclerosis, skin atrophy or ulcer, diabetes, osteoporosis, hypogonadism, and cancer. Most of the phenotypes appear in adults; however, short stature, which is reported in approximately 95% of WS cases, is evident and usually observed before the appearance of other signs and genetic diagnosis [1,2]. Children with WS have a slow growth rate, light body weight, and unusually thin extremities. ...
... Children with WS have a slow growth rate, light body weight, and unusually thin extremities. Growth spurt is absent during adolescence, and retarded body development is evident before the onset of other premature aging signs [1,2]. ...
... Full length SHOX promoters were amplified from 293 T genomic DNA using Q5 polymerase and cloned to pGL3-Basic luciferase plasmid (Promega) using SacI;HindIII and MluI;HindIII sites for promoter 1 system. pCas9-Puro were generated by Gibson assembly using PCR products of primers CP-1 on PX458 (Addgene #48138) and CP-2 on pLenti-TRE3G-BE3RA-PGK-Puro (Addgene #110846) and backbone of ClaI;NotI cut pHAGE-EF1a-IRES-zsGreen. pgRNA-GFP was constructed by inserting a gRNA cassette cloned from pDD-Cas9 (Addgene #90085) into pHAGE-EF1a-IRES-zsGreen with SpeI site. ...
Background
Pathogenic mutations in WRN are a cause of premature aging disease Werner syndrome (WS). Besides accelerated aging phenotypes and cancer predisposition, patients with WS also display underdevelopment in the skeletal system, characterized by short stature, light body weight and unusually thin extremities. The reasons for these developmental defects are not completely understood and the underlying molecular mechanism remains to be elucidated.
Results
In this study, WRN was found to modulate transcription of short stature homeobox gene SHOX . Loss of WRN resulted in insufficient expression of SHOX, the gene dose of which is critical for driving chondrocyte differentiation. WRN could bind the G-quadruplex (G4) structures in the SHOX promoter and stimulate transcription. Aberrant formation of G4 structures in WRN-deficient cells impeded normal transcription of SHOX, thus resulting in impaired chondrogenesis. Chondrogenesis could be rescued by overexpression of WRN helicase or SHOX, suggesting that SHOX is a downstream target of WRN. Gene editing of the G4 structures in the SHOX promoter could increase SHOX expression, therefore rescuing the impaired chondrogenesis in WRN-deficient cells.
Conclusions
Our data suggest that dysgenesis of the developing bone in WS might be caused by SHOX insufficiency. Aberrant formation of G4 structures in SHOX promoter suppresses SHOX expression and impairs chondrogenesis. Targeted mutagenesis in the G4 structures enhances SHOX expression and thus providing an opportunity to rescue the chondrogenic defect.
... Mutations of BLM, WRN and RECQL4 cause Bloom (BLM), Werner (WRN) and Rothmund-Thompson (RTS) syndromes, respectively. The BLM, WRN and RECQL4 proteins show nuclease domains, which support their involvement in hyper-recombination processes [145][146][147]. In addition to growth disorders and accelerated aging, these three syndromes have in common a strong predisposition to sarcoma. ...
... In addition to growth disorders and accelerated aging, these three syndromes have in common a strong predisposition to sarcoma. With regard to aging and predisposition to early senescence, it can be hypothesized that an instable helicase-endonuclease complex would be responsible of the generation of spontaneous breaks that may promote a senescence phenomenon [145][146][147]. All these syndromes are associated with significant but moderate radiosensitivity [1]. ...
There are a number of genetic syndromes associated with both high cancer risk and clinical radiosensitivity. However, the link between these two notions remains unknown. Particularly, some cancer syndromes are caused by mutations in genes involved in DNA damage signaling and repair. How are the DNA sequence errors propagated and amplified to cause cell transformation? Conversely, some cancer syndromes are caused by mutations in genes involved in cell cycle checkpoint control. How is misrepaired DNA damage produced? Lastly, certain genes, considered as tumor suppressors, are not involved in DNA damage signaling and repair or in cell cycle checkpoint control. The mechanistic model based on radiation-induced nucleoshuttling of the ATM kinase (RIANS), a major actor of the response to ionizing radiation, may help in providing a unified explanation of the link between cancer proneness and radiosensitivity. In the frame of this model, a given protein may ensure its own specific function but may also play additional biological role(s) as an ATM phosphorylation substrate in cytoplasm. It appears that the mutated proteins that cause the major cancer and radiosensitivity syndromes are all ATM phosphorylation substrates, and they generally localize in the cytoplasm when mutated. The relevance of the RIANS model is discussed by considering different categories of the cancer syndromes.
... Werner Syndrome (WS) is a rarely seen autosomal recessive early ageing syndrome; characterised by early atherosclerosis, cataracts, diabetes mellitus, hypogonadism, osteoporosis, characteristic skin changes and alopecia (Muftuoglu et al. 2008, Yamamoto et al. 2003. Although systemic ageing in the course of WS has been well documented, the effects on the central nervous system are not sufficiently known. ...
... Although systemic ageing in the course of WS has been well documented, the effects on the central nervous system are not sufficiently known. Just a few case reports have reported cerebral atrophy and psychotic symptoms (Hashimoto et al, 2006), and ıt is generally assumed that the accelerated ageing in WS patients has not reached the central nervous system and that mortality occurs because of malignancy or myocardial infarctus in the majority of patients (Muftuoglu et al. 2008, Mori et al. 2003. The case here we presented of a patient who admitted with depressive symptoms that had developed with the difficulties experienced by the patient during the course of the disease, and diagnosed with Werner syndrome in a psychiatry clinic. ...
... Interestingly, WRN protein, a helicase of the RecQ family has also been implicated in BER and in telomere preservation. Mutations in the gene encoding WRN protein cause Werner Syndrome, a rare human genetic disorder characterized by features of premature aging, predisposition to sarcoma and thyroid cancers, oxidative stress, genomic instability, and increased telomere loss (Crabbe et al., 2007;Muftuoglu et al., 2008;Croteau et al., 2014). WRN facilitates telomere replication by resolving complex DNA structures found at telomeres such as T-loops, D-loops and G4s (Opresko et al., 2004;Nora et al., 2010;Damerla et al., 2012). ...
Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA. Numerous studies have shown that oxidative stress caused by excess reactive oxygen species is associated with accelerated telomere shortening and dysfunction. Telomeric repeat sequences are remarkably susceptible to oxidative damage and are preferred sites for the production of the mutagenic base lesion 8-oxoguanine, which can alter telomere length homeostasis and integrity. Therefore, knowledge of the repair pathways involved in the processing of 8-oxoguanine at telomeres is important for advancing understanding of the pathogenesis of degenerative diseases and cancer associated with telomere instability. The highly conserved guanine oxidation (GO) system involves three specialized enzymes that initiate distinct pathways to specifically mitigate the adverse effects of 8-oxoguanine. Here we introduce the GO system and review the studies focused on investigating how telomeric 8-oxoguanine processing affects telomere integrity and overall genome stability. We also discuss newly developed technologies that target oxidative damage selectively to telomeres to investigate roles for the GO system in telomere stability.
... In addition, WRN is required for telomere maintenance and apoptosis. 60 Recessive WRN mutations account for classical WS. However, atypical forms of the disease (atypical WS) are reported, with patients showing no WRN mutations and often an early onset of the symptoms and an accelerated disease progression. ...
... 71 The WRN protein allows maintenance of genome stability during DNA replication, recombination, repair, and transcription, and is required for telomere maintenance and apoptosis. 60 Most of the mutations observed in WS patients result in the absence of a functional WRN protein in nuclei, and cells from WS patients display impaired DNA replication, chromosomal instability, telomere shortening, and premature senescence with cell passing in culture. 72 ...
Premature-ageing syndromes are a heterogeneous group of rare genetic disorders resembling features of accelerated ageing and resulting from mutations in genes coding for proteins required for nuclear lamina architecture, DNA repair and maintenance of genome stability, mitochondrial function and other cellular processes. Hutchinson–Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best-characterized progeroid syndromes referred to as childhood- and adulthood-progeria, respectively. This article provides an updated overview of the mutations leading to HGPS, WS, and to the spectrum of premature-ageing laminopathies ranging in severity from congenital restrictive dermopathy (RD) to adult-onset atypical WS, including RD-like laminopathies, typical and atypical HGPS, more and less severe forms of mandibuloacral dysplasia (MAD), Néstor-Guillermo progeria syndrome (NGPS), atypical WS, and atypical progeroid syndromes resembling features of HGPS and/or MAD but resulting from impaired DNA repair or mitochondrial functions, including mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and mandibuloacral dysplasia associated to MTX2 (MADaM). The overlapping signs and symptoms among different premature-ageing syndromes, resulting from both a large genetic heterogeneity and shared pathological pathways underlying these conditions, require an expert clinical evaluation in specialized centers paralleled by next-generation sequencing of panels of genes involved in these disorders in order to establish as early as possible an accurate clinical and molecular diagnosis for a proper patient management.
... Werner syndrome (WS) is a rare autosomal recessive premature aging disorder that begins at a young age with graying and loss of hair and cataracts, followed by accelerated aging symptoms such as diabetes, atherosclerosis, and cancer [1][2][3][4]. The median life expectancy is in the mid-50s, and most deaths are due to arteriosclerosis and malignancy [5]. ...
Werner syndrome (WS), also known as adult progeria, is characterized by accelerated aging symptoms from a young age. Patients with WS experience painful intractable skin ulcers with calcifications in their extremities, subcutaneous lipoatrophy, and sarcopenia. However, there is no significant abnormality in the trunk skin, where the subcutaneous fat relatively accumulates. The cause of such differences between the limbs and trunk is unknown. To investigate the underlying mechanism behind these phenomena, we established and analyzed dermal fibroblasts from the foot and trunk of two WS patients. As a result, WS foot-derived fibroblasts showed decreased proliferative potential compared to that from the trunk, which correlated with the telomere shortening. Transcriptome analysis showed increased expression of genes involved in osteogenesis in the foot fibroblasts, while adipogenic and chondrogenic genes were downregulated in comparison with the trunk. Consistent with these findings, the adipogenic and chondrogenic differentiation capacity was significantly decreased in the foot fibroblasts in vitro. On the other hand, the osteogenic potential was mutually maintained and comparable in the foot and trunk fibroblasts. These distinct phenotypes in the foot and trunk fibroblasts are consistent with the clinical symptoms of WS and may partially explain the underlying mechanism of this disease phenotype.
