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1.
Int J Oral Maxillofac Surg. 2019 Nov;48(11):1394-1397. doi: 10.1016/j.ijom.2019.06.005. Epub 2019 Jun 22.

Oral squamous cell carcinoma arising in a patient with Werner syndrome.

Author information

1
Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Mibu, Shimo-Tsuga, Tochigi, Japan; Section of Dentistry, Oral and Maxillofacial Surgery, Kamitsuga General Hospital, Kanuma, Tochigi, Japan. Electronic address: kuri-25@dokkyomed.ac.jp.
2
Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Mibu, Shimo-Tsuga, Tochigi, Japan.
3
Department of Dermatology, Dokkyo Medical University School of Medicine, Mibu, Shimo-Tsuga, Tochigi, Japan.

Abstract

Werner syndrome (WS) is an autosomal recessive disorder characterized by physical signs and symptoms, including premature aging and scleroderma-like skin changes. The gene responsible for WS is the WRN gene. A significant proportion of WS-related malignant tumours are non-epithelial types, and the incidence of oral squamous cell carcinoma (SCC) is rare. A case of oral SCC of the lower alveolus and gingiva arising in a 63-year-old woman with WS is reported here. Biopsy confirmed moderately differentiated SCC. Surgical resection was performed and there was no recurrence or metastasis at the 3-year follow-up. Mutation analysis using next-generation sequencing, detected no mutations in the genes encoding the molecules strongly involved in the development of oral SCC, such as TP53 or PIK3CA. No obvious mutations were detected. Based on the results of the study, the results of mutation analysis suggest that this case might be genetically different from the common mechanisms of SCC in the oral cavity.

KEYWORDS:

Werner syndrome; oral cancer; squamous cell carcinoma

PMID:
31235391
DOI:
10.1016/j.ijom.2019.06.005
[Indexed for MEDLINE]
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2.
Nucleic Acids Res. 2019 Jul 26;47(13):6796-6810. doi: 10.1093/nar/gkz431.

RAD51 and mitotic function of mus81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease.

Author information

1
Mechanisms, Biomarkers and Models Unit, Department of Environment and Health, Istituto Superiore di Sanità, Roma, Italy.
2
Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA 91010-3000, USA.
3
Braun Laboratories, California Institute of Technology, Pasadena, CA 91125, USA.
4
Istituto Nazionale Biostrutture e Biosistemi, Roma, Italy.

Abstract

Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death.

PMID:
31114910
PMCID:
PMC6648349
DOI:
10.1093/nar/gkz431
[Indexed for MEDLINE]
Free PMC Article
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3.
Nature. 2019 Apr;568(7753):511-516. doi: 10.1038/s41586-019-1103-9. Epub 2019 Apr 10.

Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.

Author information

1
Wellcome Sanger Institute, Cambridge, UK.
2
Open Targets, Cambridge, UK.
3
European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, UK.
4
Candiolo Cancer Institute-FPO, IRCCS, Turin, Italy.
5
Department of Oncology, University of Torino, Turin, Italy.
6
GlaxoSmithKline Research and Development, Stevenage, UK.
7
GlaxoSmithKline Research and Development, Collegeville, PA, USA.
8
Faculty of Medicine, Joint Research Centre for Computational Biomedicine, RWTH Aachen University, Aachen, Germany.
9
Institute for Computational Biomedicine, Heidelberg University, Faculty of Medicine, Bioquant, Heidelberg, Germany.
10
Heidelberg University Hospital, Heidelberg, Germany.
11
Wellcome Sanger Institute, Cambridge, UK. k.yusa@infront.kyoto-u.ac.jp.
12
Open Targets, Cambridge, UK. k.yusa@infront.kyoto-u.ac.jp.
13
Stem Cell Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. k.yusa@infront.kyoto-u.ac.jp.
14
Wellcome Sanger Institute, Cambridge, UK. mathew.garnett@sanger.ac.uk.
15
Open Targets, Cambridge, UK. mathew.garnett@sanger.ac.uk.

Abstract

Functional genomics approaches can overcome limitations-such as the lack of identification of robust targets and poor clinical efficacy-that hamper cancer drug development. Here we performed genome-scale CRISPR-Cas9 screens in 324 human cancer cell lines from 30 cancer types and developed a data-driven framework to prioritize candidates for cancer therapeutics. We integrated cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritize new targets in defined tissues and genotypes. We verified one of our most promising dependencies, the Werner syndrome ATP-dependent helicase, as a synthetic lethal target in tumours from multiple cancer types with microsatellite instability. Our analysis provides a resource of cancer dependencies, generates a framework to prioritize cancer drug targets and suggests specific new targets. The principles described in this study can inform the initial stages of drug development by contributing to a new, diverse and more effective portfolio of cancer drug targets.

PMID:
30971826
DOI:
10.1038/s41586-019-1103-9
[Indexed for MEDLINE]
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4.
Nucleic Acids Res. 2019 Apr 23;47(7):3485-3502. doi: 10.1093/nar/gkz025.

ATM pathway activation limits R-loop-associated genomic instability in Werner syndrome cells.

Author information

1
Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.
2
Department of Cell Biology and Neurosciences, Section of Gene and Cell Therapy, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.

Abstract

Werner syndrome (WS) is a cancer-prone disease caused by deficiency of Werner protein (WRN). WRN maintains genome integrity by promoting replication-fork stability after various forms of replication stress. Under mild replication stress, WS cells show impaired ATR-mediated CHK1 activation. However, it remains unclear if WS cells elicit other repair pathway. We demonstrate that loss of WRN leads to enhanced ATM phosphorylation upon prolonged exposure to aphidicolin, a specific inhibitor of DNA polymerases, resulting in CHK1 activation. Moreover, we find that loss of WRN sensitises cells to replication-transcription collisions and promotes accumulation of R-loops, which undergo XPG-dependent cleavage responsible for ATM signalling activation. Importantly, we observe that ATM pathway limits chromosomal instability in WS cells. Finally, we prove that, in WS cells, genomic instability enhanced upon chemical inhibition of ATM kinase activity is counteracted by direct or indirect suppression of R-loop formation or by XPG abrogation. Together, these findings suggest a potential role of WRN as regulator of R-loop-associated genomic instability, strengthening the notion that conflicts between replication and transcription can affect DNA replication, leading to human disease and cancer.

PMID:
30657978
PMCID:
PMC6468170
DOI:
10.1093/nar/gkz025
[Indexed for MEDLINE]
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5.
Intern Med. 2019 Apr 1;58(7):1033-1036. doi: 10.2169/internalmedicine.1816-18. Epub 2018 Dec 18.

Characteristic Clinical Features of Werner Syndrome with a Novel Compound Heterozygous WRN Mutation c.1720+1G>A Plus c.3139-1G>C.

Author information

1
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.
2
Department of Neurology, Okayama Citizen's Hospital, Japan.
3
Department of General Internal Medicine, Okayama Citizen's Hospital, Japan.
4
Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Japan.
5
Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, Japan.
6
Department of Pathology, University of Washington, USA.

Abstract

Werner syndrome (WS) is an autosomal recessive progeroid disorder caused by mutations in the WRN gene (WRN). Most Japanese WS patients are born from a consanguineous marriage with homozygous WRN mutations. We herein report a rare WS patient born from non-consanguineous parents with compound heterozygous WRN mutations with a novel heterogeneous c.1720+1G>A substitution plus the most frequent heterogeneous c.3139-1G>C substitution among Japanese. Although the present case showed clinical characteristics common to previous Japanese WS patients, he had not developed any malignant tumors as of 43 years of age, suggesting that WS patients with this particular genetic mutation have a different phenotype than others.

KEYWORDS:

Japanese; compound heterozygous; werner syndrome

PMID:
30568144
PMCID:
PMC6478977
DOI:
10.2169/internalmedicine.1816-18
[Indexed for MEDLINE]
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6.
Oncogene. 2019 Apr;38(14):2501-2515. doi: 10.1038/s41388-018-0605-5. Epub 2018 Dec 7.

MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner.

Author information

1
Department of Medical Genetics, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, China.
2
Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
3
Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, China.
4
Department of Medical Genetics, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, China. luojianyuan@bjmu.edu.cn.

Abstract

MDM2 (Murine double minute 2) acts as a key repressor for p53-mediated tumor-suppressor functions, which includes cellular senescence. We found that MDM2 can promote cellular senescence by modulating WRN stability. Werner syndrome (WS), caused by mutations of the WRN gene, is an autosomal recessive disease, which is characterized by premature aging. Loss of WRN function induces cellular senescence in human cancer cells. Here, we found that MDM2 acts as an E3 ligase for WRN protein. MDM2 interacts with WRN both in vivo and in vitro. MDM2 induces ubiquitination of WRN and dramatically downregulates the levels of WRN protein in human cells. During DNA damage response, WRN is translocated to the nucleoplasm to facilitate its DNA repair functions; however, it is degraded by the MDM2-mediated ubiquitination pathway. Moreover, the senescent phenotype induced by DNA damage reagents, such as Etoposide, is at least in part mediated by MDM2-dependent WRN degradation as it can be significantly attenuated by ectopic expression of WRN. These results show that MDM2 is critically involved in regulating WRN function via ubiquitin-dependent degradation and reveal an unexpected role of MDM2 in promoting cellular senescence through a p53-independent manner.

PMID:
30532073
DOI:
10.1038/s41388-018-0605-5
[Indexed for MEDLINE]
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7.
DNA Repair (Amst). 2019 Jan;73:17-27. doi: 10.1016/j.dnarep.2018.10.005. Epub 2018 Oct 28.

Werner syndrome (WRN) DNA helicase and base excision repair (BER) factors maintain endothelial homeostasis.

Author information

1
Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225, Düsseldorf, Germany. Electronic address: Kathrin.Laarmann@uni-duesseldorf.de.
2
Institute of Toxicology, University Medical Center Mainz, Obere Zahlbacher Str. 67, D-55131, Mainz, Germany. Electronic address: joakress@uni-mainz.de.
3
Institute of Toxicology, University Medical Center Mainz, Obere Zahlbacher Str. 67, D-55131, Mainz, Germany. Electronic address: kaina@uni-mainz.de.
4
Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225, Düsseldorf, Germany. Electronic address: fritz@uni-duesseldorf.de.

Abstract

The accelerated ageing disease Werner Syndrome (WRN) is characterized by pronounced atherosclerosis. Here, we investigated the influence of WRN downregulation on the functionality of non-replicating human endothelial cells. RNAi-mediated downregulation of WRN reduces cell motility and enhances the expression of factors regulating adhesion, inflammation, hemostasis and vasomotor tone. Moreover, WRN influences endothelial barrier function and Ca2+-release, while cell adhesion, Dil-acLDL-uptake and the mRNA expression of NO-synthases (eNOS, iNOS) remained unaffected. Regarding motility, we propose that WRN affects Rac1/FAK/ß1-integrin-related mechanisms regulating cell polarity and directed motility. Since oxidative DNA base damage contributes to aging and atherosclerosis and WRN affects DNA repair, we investigated whether downregulation of base excision repair (BER) factors mimics the effects of WRN knock-down. Indeed, downregulation of particular WRN-interacting base excision repair (BER) proteins (APE1, NEIL1, PARP1) imitates the inhibitory effect of WRN on motility. Knock-down of OGG1, which does not interact with WRN, does not influence motility but increases the mRNA expression of E-selectin, ICAM, VCAM, CCL2 and VEGFR and stimulates adhesion. Thus, individual BER factors themselves differently impact endothelial cell functionality and homeostasis. Impairment of endothelial activities caused by genotoxic stressor (tBHQ) remained largely unaffected by WRN. Summarizing, both WRN, WRN-associated BER proteins and OGG1 promote the maintenance of endothelial cell homeostasis, thereby counteracting the development of ageing-related endothelial malfunction in non-proliferating endothelial cells.

KEYWORDS:

Base excision repair (BER); Endothelial homeostasis; Non-replicating cells; Oxidative stress; WRN helicase

PMID:
30413344
DOI:
10.1016/j.dnarep.2018.10.005
[Indexed for MEDLINE]
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8.
Mol Genet Genomic Med. 2018 Nov;6(6):1148-1156. doi: 10.1002/mgg3.495. Epub 2018 Nov 4.

CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures.

Author information

1
Department of Pathology, University of Washington, Seattle, Washington.
2
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
3
Sarah Network of Rehabilitation Hospitals, Belo Horizonte, Brazil.
4
Discipline of Genetic Medicine, Westmead Clinical School, Sydney Faculty of Medicine and Health, Westmead, Australia.
5
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.
6
Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.

Abstract

BACKGROUND:

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis and replication.

METHODS:

A Brazilian pedigree and an Australian pedigree were referred to the International Registry of Werner Syndrome (Seattle, WA, USA), with clinical features of accelerated aging and recurrent bone fractures. Whole exome sequencing was performed to identify the genetic causes.

RESULTS:

Whole exome sequencing of the Brazilian pedigree revealed compound heterozygous pathogenic variants in CTC1: a missense mutation (c.2959C>T, p.Arg987Trp) and a novel stop codon change (c.322C>T, p.Arg108*). The Australian patient carried two novel heterozygous CTC1 variants, c.2916G>T, p.Val972Gly and c.2926G>T, p.Val976Phe within the same allele. Both heterozygous variants were inherited from the unaffected father, excluding the diagnosis of CRMCC in this pedigree. Cell biological studies demonstrated accumulation of double strand break foci in lymphoblastoid cell lines derived from the patients. Increased DSB foci were extended to non-telomeric regions of the genome, in agreement with previous biochemical studies showing a preferential binding of CTC1 protein to GC-rich sequences.

CONCLUSION:

CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. Further studies are needed to elucidate the disease mechanism leading to the clinical presentation with intra-familial variations of CRMCC.

KEYWORDS:

CTC1; Mendelian disorders; genomic instability; molecular genetics; progeroid syndrome; telomeres

PMID:
30393977
PMCID:
PMC6305643
DOI:
10.1002/mgg3.495
[Indexed for MEDLINE]
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9.
Cell Death Dis. 2018 Sep 11;9(9):923. doi: 10.1038/s41419-018-0948-4.

Ectopic hTERT expression facilitates reprograming of fibroblasts derived from patients with Werner syndrome as a WS cellular model.

Author information

1
Cell Therapy Center, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China.
2
Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China.
3
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
4
Division of Hematology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
5
Department of Pathology, Shandong University School of Medicine, Jinan, China.
6
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
7
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
8
Division of Hematology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. Dawei.Xu@ki.se.
9
Cell Therapy Center, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China. chenzhiguo@gmail.com.
10
Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China. chenzhiguo@gmail.com.

Abstract

The induced pluripotent stem cell (iPSC) technology has provided a unique opportunity to develop disease-specific models and personalized treatment for genetic disorders, and is well suitable for the study of Werner syndrome (WS), an autosomal recessive disease with adult onset of premature aging caused by mutations in the RecQ like helicase (WRN) gene. WS-derived fibroblasts were previously shown to be able to generate iPSCs; however, it remains elusive how WS-derived iPSCs behave and whether they are able to mimic the disease-specific phenotype. The present study was designed to address these issues. Unexpectedly, we found that a specific WS fibroblast line of homozygous truncation mutation was difficult to be reprogrammed by using the Yamanaka factors even under hypoxic conditions due to their defect in induction of hTERT, the catalytic unit of telomerase. Ectopic expression of hTERT restores the ability of this WS fibroblast line to form iPSCs, although with a low efficiency. To examine the phenotype of WRN-deficient pluripotent stem cells, we also generated WRN knockout human embryonic stem (ES) cells by using the CRISPR/Cas9 method. The iPSCs derived from WS-hTERT cells and WRN-/- ESCs are fully pluripotent, express pluripotent markers and can differentiate into three germ layer cells; however, WS-iPSCs and WRN-/- ESCs show S phase defect in cell cycle progression. Moreover, WS-iPSCs and WRN-/- ESCs, like WS patient-derived fibroblasts, remain hypersensitive to topoisomerase inhibitors. Collectively, WS-derived iPSCs and WRN-/- ESCs mimic the intrinsic disease phenotype, which may serve as a suitable disease model, whereas not be good for a therapeutic purpose without gene correction.

PMID:
30206203
PMCID:
PMC6134116
DOI:
10.1038/s41419-018-0948-4
[Indexed for MEDLINE]
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10.
Intern Med. 2019 Jan 1;58(1):109-113. doi: 10.2169/internalmedicine.0317-17. Epub 2018 Aug 24.

Successful Cord Blood Transplantation in a Werner Syndrome Patient with High-risk Myelodysplastic Syndrome.

Author information

1
Department of Hematology, Kawasaki Medical School, Japan.
2
Department of Transfusion Medicine, Saitama Medical Center, Saitama Medical University, Japan.
3
Department of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Japan.
4
Department of Rheumatology/Orthopedic Surgery, East Medical Center, Tokyo Women's Medical University, Japan.
5
Department of Pathology, Kawasaki Medical School, Japan.

Abstract

Werner syndrome (WS) confers a high risk of the development of neoplasias, including hematological malignancies, and curative treatment for these malignancies is difficult to achieve. A 44-year-old man with myelodysplastic syndrome was admitted to our hospital. He was diagnosed with mutation-proven WS. He underwent cord blood transplantation (CBT) following fludarabine, busulfan, and melphalan administration. A chimerism analysis of his marrow blood on day 62 showed a donor pattern >95%, which confirmed engraftment. The patient lived for 15 months while maintaining remission of MDS without treatment-related toxicity. Our case shows that CBT can be a treatment modality for WS patients with hematological malignancies.

KEYWORDS:

Werner syndrome; cord blood transplantation; myelodysplastic syndrome

PMID:
30146558
PMCID:
PMC6367075
DOI:
10.2169/internalmedicine.0317-17
[Indexed for MEDLINE]
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11.
Mutagenesis. 2018 Oct 11;33(4):301-310. doi: 10.1093/mutage/gey024.

Mutations induced by 8-oxo-7,8-dihydroguanine in WRN- and DNA polymerase λ-double knockdown cells.

Author information

1
Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
2
Graduate School of Science and Engineering, Ehime University, Matsuyama, Japan.
3
College of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Japan.

Abstract

Reactive oxygen species generate 8-oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine), which induces G:C→T:A transversion mutations. The knockdowns of the protein responsible for Werner syndrome (WRN), a cancer-associated DNA helicase, and DNA polymerase (pol) λ, a WRN-interacting DNA pol, cause untargeted base-substitution mutations (action-at-a-distance mutations). To examine the consequences of the dual reductions of WRN and pol λ for the mutations caused by GO, siRNAs against both proteins were introduced into human U2OS cells. A replicable plasmid DNA with the oxidised nucleobase in a unique position of the supF gene was then introduced into the double knockdown cells. The amplified DNA recovered from the cells was used to transform a bacterial indicator strain. The mutant frequency and the subsequent sequence analysis revealed that the double knockdown additively promoted the G:C→T:A substitution at the GO position and increased the action-at-a-distance mutations to a level similar to that of the single WRN knockdown. Thus, WRN and DNA pol λ seem to suppress the targeted G:C→T:A mutation at least in part independently and reduce the untargeted mutations via an identical pathway.

PMID:
30137433
DOI:
10.1093/mutage/gey024
[Indexed for MEDLINE]
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12.
Indian J Ophthalmol. 2018 Sep;66(9):1337-1339. doi: 10.4103/ijo.IJO_1308_17.

Management of cataract in Werner syndrome.

Author information

1
Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India.

Abstract

Werner syndrome (WS) is a rare progressive disorder. It is characterized by the appearance of unusually accelerated aging (progeria) including bilateral senile cataract. Here, we report a successful management of hypermature cataract in WS.

KEYWORDS:

Cataract; Werner syndrome; progeria

PMID:
30127165
PMCID:
PMC6113835
DOI:
10.4103/ijo.IJO_1308_17
[Indexed for MEDLINE]
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13.
BMC Ophthalmol. 2018 Aug 14;18(1):199. doi: 10.1186/s12886-018-0873-4.

A case report of Werner's syndrome with bilateral juvenile cataracts.

Author information

1
Department of Ophthalmology, Shengli Oilfield Central Hospital, Shandong Province, Dongying, 257000, China.
2
Department of Ophthalmology, Tianjin Medical University Eye Hospital, Tianjin, 30000, China.
3
Vitreous & Retinal Department, Apex Eye Hospital, Xincai, 463500, Henan Province, China.
4
Department of Ophthalmology, Xin Hua Hospital Affiliate of Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
5
Department of Ophthalmology, Shengli Oilfield Central Hospital, Shandong Province, Dongying, 257000, China. 13905461351@139.com.
6
Department of Ophthalmology, Shengli Oilfield Central Hospital, Shandong Province, Dongying, 257000, China. dongyingjxg@163.com.

Abstract

BACKGROUND:

To report a case of Werner's syndrome with bilateral juvenile cataracts.

CASE PRESENTATION:

Review of the clinical, laboratory, photographic, genetic testing of the patient. A 26-year-old Chinese man presented with impaired vision in both eyes for more than a year. Anterior segment examination of both eyes revealed cataract. According to the ocular symptoms and systemic signs, including low body weight, a short stature, a bird-like face, atrophic and scleroderma-like skin, in addition to the juvenile cataracts, the clinical diagnosis of Werner's syndrome was made. Next-generation sequencing identified a homozygous WRN mutation in this patient.

CONCLUSIONS:

The ocular and systemic findings in this patient in combination with the homozygous WRN mutation indicated the definitive Werner's syndrome diagnosis.

KEYWORDS:

Premature aging; WRN mutation; Werner’s syndrome

PMID:
30107835
PMCID:
PMC6092780
DOI:
10.1186/s12886-018-0873-4
[Indexed for MEDLINE]
Free PMC Article
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15.
An Bras Dermatol. 2018 Jun;93(3):443-446. doi: 10.1590/abd1806-4841.20187517.

Recurrent skin ulcer cross-repair and sensory reconstruction in a WRN gene mutational patient.

Author information

1
Xiangya Hospital, Central South University, Changsha, China.

Abstract

A 37-year-old man complained of a refractory posterior malleolar ulceration on his left ankle. He was diagnosed with Werner syndrome according to the progeroid clinical features and genetic testing. To approach the ulceration, a free flow-through right anterolateral thigh perforator flap with anterolateral thigh cutaneous nerve was harvested. One year later, he was readmitted due to a new ulceration on his right ankle. We harvested the left anterolateral thigh perforator flap with anterolateral thigh cutaneous nerve to reconstruct the defect. After one more year of follow-up, there was no recurrence of ulcers, and the sensation of the flap recovered partially after 6 months. We conclude that free flow-through anterolateral thigh perforator flap is a feasible choice for the repair of foot ulcers in Werner syndrome.

PMID:
29924215
PMCID:
PMC6001081
DOI:
10.1590/abd1806-4841.20187517
[Indexed for MEDLINE]
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16.
Brain Behav Immun. 2018 Oct;73:450-469. doi: 10.1016/j.bbi.2018.06.007. Epub 2018 Jun 15.

Nonfunctional mutant Wrn protein leads to neurological deficits, neuronal stress, microglial alteration, and immune imbalance in a mouse model of Werner syndrome.

Author information

1
Axe neurosciences, Centre de recherche du CHU de Québec, Centre Hospitalier de l'Université Laval (CHUL), 2705 Laurier Blvd., Québec City, Québec G1V 4G2, Canada.
2
Axe endocrinologie/néphrologie, Centre de recherche du CHU de Québec, Centre Hospitalier de l'Université Laval (CHUL), 2705 Laurier Blvd., Québec City, Québec G1V 4G2, Canada.
3
Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec City, Québec G1V 4G5, Canada.
4
Axe endocrinologie/néphrologie, Centre de recherche du CHU de Québec, Centre Hospitalier de l'Université Laval (CHUL), 2705 Laurier Blvd., Québec City, Québec G1V 4G2, Canada. Electronic address: michel.lebel@crchudequebec.ulaval.ca.
5
Axe neurosciences, Centre de recherche du CHU de Québec, Centre Hospitalier de l'Université Laval (CHUL), 2705 Laurier Blvd., Québec City, Québec G1V 4G2, Canada. Electronic address: tremblay.marie-eve@crchudequebec.ulaval.ca.

Abstract

Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter lifespan. Yet, little is known about the impact of WRN mutations on the central nervous system in both humans and mouse models of WS. In the current study, we have performed a longitudinal behavioral assessment on mice bearing a Wrn helicase deletion. Behavioral tests demonstrated a loss of motor activity and coordination, reduction in perception, increase in repetitive behavior, and deficits in both spatial and social novelty memories in Wrn mutant mice compared to age-matched wild type mice. These neurological deficits were associated with biochemical and histological changes in the brain of aged Wrn mutant mice. Microglia, resident immune cells that regulate neuronal plasticity and function in the brain, were hyper-ramified in multiple regions involved with the behavioral deficits of Wrn mutant mice. Furthermore, western analyses indicated that Wrn mutant mice exhibited an increase of oxidative stress markers in the prefrontal cortex. Supporting these findings, electron microscopy studies revealed increased cellular aging and oxidative stress features, among microglia and neurons respectively, in the prefrontal cortex of aged Wrn mutant mice. In addition, multiplex immunoassay of serum identified significant changes in the expression levels of several pro- and anti-inflammatory cytokines. Taken together, these findings indicate that microglial dysfunction and neuronal oxidative stress, associated with peripheral immune system alterations, might be important driving forces leading to abnormal neurological symptoms in WS thus suggesting potential therapeutic targets for interventions.

KEYWORDS:

Behavior; Brain; Cytokines; Microglia; Mouse aging; Neuron; Oxidative stress; Werner syndrome

PMID:
29908963
DOI:
10.1016/j.bbi.2018.06.007
[Indexed for MEDLINE]
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17.
Rheumatology (Oxford). 2018 Nov 1;57(11):2021. doi: 10.1093/rheumatology/key163.

Werner syndrome: a rare cause of osteoporosis in a young female.

Author information

1
Department of Rheumatology, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
2
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
PMID:
29878212
DOI:
10.1093/rheumatology/key163
[Indexed for MEDLINE]
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18.
DNA Repair (Amst). 2018 Aug;68:1-11. doi: 10.1016/j.dnarep.2018.05.003. Epub 2018 May 18.

Acidic domain of WRNp is critical for autophagy and up-regulates age associated proteins.

Author information

1
Department of Life Science and Biotechnology, Jadavpur University, Kolkata, 700032, India.
2
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
3
Department of Life Science and Biotechnology, Jadavpur University, Kolkata, 700032, India. Electronic address: parimal.karmakar@jadavpuruniversity.in.

Abstract

Impaired autophagy may be associated with normal and pathological aging. Here we explore a link between autophagy and domain function of Werner protein (WRNp). Werner (WRN) mutant cell lines AG11395, AG05229 and normal aged fibroblast AG13129 display a deficient response to tunicamycin mediated endoplasmic reticulum (ER) stress induced autophagy compared to clinically unaffected GM00637 and normal young fibroblast GM03440. Cellular endoplasmic reticulum (ER) stress mediated autophagy in WS and normal aged cells is restored after transfection with wild type full length WRN, but deletion of the acidic domain from wild type WRN fails to restore autophagy. The acidic domain of WRNp was shown to regulate its transcriptional activity, and here, we show that it affects the transcription of certain proteins involved in autophagy and aging. Furthermore, siRNA mediated silencing of WRN in normal fibroblast WI-38 resulted in decrease of age related proteins Lamin A/C and Mre11.

KEYWORDS:

Acidic domain; Aging; Autophagy; Beclin-1; Endoplasmic reticulum; RecQ helicase; Werner protein; Werner syndrome

PMID:
29800817
PMCID:
PMC6338341
DOI:
10.1016/j.dnarep.2018.05.003
[Indexed for MEDLINE]
Free PMC Article
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19.
Int Ophthalmol. 2019 Jun;39(6):1371-1378. doi: 10.1007/s10792-018-0929-8. Epub 2018 Apr 28.

The ophthalmic diagnosis and management of four siblings with Werner syndrome.

Author information

1
Department of Ophthalmology, University Hospital Galway, University Road, Galway, Ireland. clyons87@gmail.com.
2
Department of Ophthalmology, University Hospital Galway, University Road, Galway, Ireland.

Abstract

INTRODUCTION:

Werner syndrome is a rare autosomal recessive disorder caused by mutations in the Werner syndrome WRN gene, on chromosome 8. Those affected manifest early the features of ageing.

DISCUSSION:

Cataract surgery is prone to post-operative complications in those with Werner syndrome. The development of cystoid macular oedema (CMO) is likely multifactorial. Patients with WS have diabetes mellitus type 2 which can contribute to macular oedema. There is a deposition of abnormal WRN proteins in the macula which also predisposes to macular oedema. The trauma of cataract surgery appears to be the main stimulus for the development of CMO. CMO may, as a result, be difficult to manage in Werner syndrome patients.

CONCLUSION:

Further study is needed to elucidate the precise role of retinal WRN protein expression in the development of CMO in those with Werner syndrome. A tailored and more successful approach to the treatment of CMO in such patients may result.

KEYWORDS:

Cataract; Cystoid macular oedema; Werner syndrome

PMID:
29705892
DOI:
10.1007/s10792-018-0929-8
[Indexed for MEDLINE]
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20.
Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4206-4211. doi: 10.1073/pnas.1802811115. Epub 2018 Mar 26.

Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts.

Author information

1
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
2
Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903.
3
Department of Anesthesia, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
4
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; collinsf@mail.nih.gov.

Abstract

LMNA encodes the A-type lamins that are part of the nuclear scaffold. Mutations in LMNA can cause a variety of disorders called laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), atypical Werner syndrome, and Emery-Dreifuss muscular dystrophy. Previous work has shown that treatment of HGPS cells with the mTOR inhibitor rapamycin or with the rapamycin analog everolimus corrects several of the phenotypes seen at the cellular level-at least in part by increasing autophagy and reducing the amount of progerin, the toxic form of lamin A that is overproduced in HGPS patients. Since other laminopathies also result in production of abnormal and potentially toxic lamin proteins, we hypothesized that everolimus would also be beneficial in those disorders. To test this, we applied everolimus to fibroblast cell lines from six laminopathy patients, each with a different mutation in LMNA Everolimus treatment increased proliferative ability and delayed senescence in all cell lines. In several cell lines, we observed that with treatment, there is a significant improvement in nuclear blebbing, which is a cellular hallmark of HGPS and other lamin disorders. These preclinical results suggest that everolimus might have clinical benefit for multiple laminopathy syndromes.

KEYWORDS:

everolimus; lamin; laminopathies; mTOR; progeria

PMID:
29581305
PMCID:
PMC5910873
DOI:
10.1073/pnas.1802811115
[Indexed for MEDLINE]
Free PMC Article
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