Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Werner syndrome is a genetic disease characterized by early ageing, excess cancer risk, high incidence of type II diabetes mellitus, early atherosclerosis, ocular cataracts, and osteoporosis. The protein encoded by the defective gene, WRN (WRNp) associates with three activities, that is, a RecQ DNA helicase, 3'-5'-exonuclease and ATPase activities. By highlighting the DNA helicase activity, a widespread consensus in WS-associated defect(s) has been established, pointing toward a deficiency in maintaining DNA integrity. However, a possible involvement of redox pathways in WS may be suggested by several lines of evidence that include: (i) the multiple functions and interactions of WRNp with oxidative stress-related activities and factors; (ii) the pleiotropic WS clinical phenotype encompassing a number of oxidative stress-related pathologies; (iii) redox-related toxicity mechanisms of several xenobiotics exerting excess toxicity in WS cells; (iv) recent in vivo and in vitro findings of redox abnormalities in WS patients and in WS cells. The working hypothesis is raised that a deficiency in WRNp, and the pleiotropic clinical phenotype in WS patients may provide the basis to envision an underlying in vivo prooxidant state, which causes oxidative damage to biomolecules, with multiple oxidative stress-related alterations, resulting in multi-faceted clinical consequences.
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PMID:Multiple involvement of oxidative stress in Werner syndrome phenotype. 1633 57

Werner syndrome (WS) is a pleiotropic disease of premature aging involving short stature, tight, atrophied, and/or ulcerated skin; a characteristic 'birdlike' facies and high, squeaky or hoarse voice; premature greying and thinning of the hair; and early onset cataracts. Additional common symptoms include diabetes mellitus, hypogonadism, osteoporosis, osteosclerosis of the digits, soft tissue calcification, premature atherosclerosis, rare or multiple neoplasms, malformed teeth, and flat feet. Diagnosis can be difficult due to the variable presentation and rarity of the disorder. Transmission is usually autosomal recessive. The WS gene, WRN, is member of the RecQ DNA helicase family. Biallelic mutations of WRN are responsible for most patients. Although heterozygous missense mutations in the LMNA gene have been observed in severely affected WS patients, this only accounts for a small fraction of non-WRN patients. Eighteen WS cases were referred to us for molecular analysis. Eleven had definite and three had probable WS according to the University of Washington Registry clinical criteria. All exons of the WRN gene and their splice junctions were sequenced. Of the fourteen definite or probable cases, 11 had one or more WRN mutation. Thirteen different mutations were found, and ten of these were previously undescribed. There were few phenotypic differences between patients with WRN mutation(s) and those who met clinical criteria though lacking WRN mutations. However, patients with mutations tended to have more symptoms overall, and mutations were not observed in the two cases with cardiomyopathy.
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PMID:Werner syndrome and mutations of the WRN and LMNA genes in France. 1678 14

Werner syndrome is a premature aging disease characterized by genomic instability and increased cancer risk. Here, we report a 45-year-old diabetic man as the first Werner syndrome patient found to have an adiponectin gene mutation. Showing graying and loss of hair, skin atrophy, and juvenile cataract, he was diagnosed with Werner syndrome type 4 by molecular analysis. His serum adiponectin concentration was low. In the globular domain of the adiponectin gene, I164T in exon 3 was detected. When we examined effects of pioglitazone (15 mg/day) on serum adiponectin multimer and monomer concentrations using selective assays, the patient's relative percentage increased in adiponectin concentration was almost same as that in the 18 diabetic patients without an adiponectin mutation, but the absolute adiponectin concentration was half of those seen in diabetic patients treated with the same pioglitazone dose who had no adiponectin mutation. The response suggested that pioglitazone treatment might help to prevent future Werner syndrome-related acceleration of atherosclerosis. Present and further clinical relevant to atherosclerosis in this patient should be imformative concerning the pathogenesis and treatment of atherosclerosis in the presence of hypoadiponectinemia and insulin resistance.
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PMID:A patient with Werner syndrome and adiponectin gene mutation. 1680 59

Werner syndrome (WS) is a premature aging disorder that is widely used as a model for some aspects of the normal human aging process. Individuals with WS have several of the characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. In addition, WS is associated with high levels of inflammatory diseases such as atherosclerosis and type II diabetes. Recent data have indicated that fibroblasts derived from individuals with WS have activated a major molecular pathway involved in inflammation. This observation ties in with the presence of high plasma levels of inflammatory cytokines in individuals with WS. In this paper, the authors discuss the possibility that WS is an example of "inflamm-aging," in that many of the phenotypic manifestations may result from an increased inflammatory state. Moreover, drugs that specifically block this inflammation pathway may be possible candidates for therapeutic intervention in WS.
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PMID:Werner Syndrome as an example of inflamm-aging: possible therapeutic opportunities for a progeroid syndrome? 1685 81

The Werner syndrome helicase (WRN) participates in DNA replication, double strand break repair, telomere maintenance, and p53 activation. Mutations of wrn cause Werner syndrome (WS), an autosomal recessive premature aging disorder associated with cancer predisposition, atherosclerosis, and other aging related symptoms. Here, we report that WRN is a novel cofactor for HIV-1 replication. Immortalized human WRN(-/-) WS fibroblasts, lacking a functional wrn gene, are impaired for basal and Tat-activated HIV-1 transcription. Overexpression of wild-type WRN transactivates the HIV-1 long terminal repeat (LTR) in the absence of Tat, and WRN cooperates with Tat to promote high-level LTR transactivation. Ectopic WRN induces HIV-1 p24(Gag) production and retroviral replication in HIV-1-infected H9(HIV-1IIIB) lymphocytes. A dominant-negative helicase-minus mutant, WRN(K577M), inhibits LTR transactivation and HIV-1 replication. Inhibition of endogenous WRN, through co-expression of WRN(K577M), diminishes recruitment of p300/CREB-binding protein-associated factor (PCAF) and positive transcription elongation factor b (P-TEFb) to Tat/transactivation response-RNA complexes, and immortalized WRN(-/-) WS fibroblasts exhibit comparable defects in recruitment of PCAF and P-TEFb to the HIV-1 LTR. Our results demonstrate that WRN is a novel cellular cofactor for HIV-1 replication and suggest that the WRN helicase participates in the recruitment of PCAF/P-TEFb-containing transcription complexes. WRN may be a plausible target for antiretroviral therapy.
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PMID:The Werner syndrome helicase is a cofactor for HIV-1 long terminal repeat transactivation and retroviral replication. 1731 67

Werner's syndrome (adult onset progeria) is a rare form of autosomal recessive genodermatosis associated in almost 80% of cases with mutation of the WRN gene. This prototype of rapid ageing syndromes is characterized by short stature with skin and hair anomalies (early graying of the hair, alopecia, depilation, sclerosed skin), orthopedic complications (flat foot, hallux valgus and other joint deformations) as well as systemic signs (early cataract, premature and diffuse atherosclerosis, endocrinopathies) and high risk of certain types of cancer (sarcomas, myeloid blood dyscrasias). Death occurs around the age of 40 - 50 years mainly as a result of cardiovascular accident or development of a malignant tumour. Signs of early aging should evoke this basic diagnosis and arrangements should be made for appropriate follow-up with screening for and treatment of systemic complications.
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PMID:[Werner's syndrome (adult onset progeria)]. 1737 9

Werner syndrome (WS) is a premature aging disorder used as a model of normal human aging. WS individuals have several characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. Additionally, WS individuals have high levels of inflammatory diseases, such as atherosclerosis and type 2 diabetes. The in vivo aging in WS is associated with accelerated aging of fibroblasts in culture. The cause of the accelerated senescence is not understood, but may be due to the genomic instability that is a hallmark of WS. Genome instability results in activation of stress kinases, such as p38, and the p38-specific inhibitor SB203580, prevents the accelerated senescence seen in WS fibroblasts. However, oxidative damage plays a role, as low oxygen conditions and antioxidant treatment revert some of the accelerated senescence phenotype. The effects of oxidative stress appear to be suppressible by SB203580; however, it does not appear to be transduced by p38. As SB203580 is known to inhibit other kinases in addition to p38, this suggests that more than one kinase pathway is involved. The recent development of p38 inhibitors with different binding properties, specificities, and oral bioavailability, and of new potent and selective inhibitors of JNK and MK2, will make it possible to dissect the roles of various kinase pathways in the accelerated senescence of WS cells. If this accelerated senescence is reflective of WS aging in vivo, these kinase inhibitors may well form the basis of antiaging therapies for individuals with WS.
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PMID:The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging. 1746 Feb 11

Werner syndrome (WS, MIM#277700) is a very rare autosomal recessive disorder. WS clinical signs include altered distribution of subcutaneous fat, juvenile bilateral cataracts, a mask-like face and bird-like nose, trophic ulcers of the feet, diabetes mellitus, and premature atherosclerosis. The habitus is characteristic, with short stature, stocky trunk and slender extremities. WS frequency has been roughly estimated to be 1: 100,000 in Japan and 1: 1,000,000-1: 10,000,000 outside of Japan. The only exception to the latter data can be seen in the clustering of WS in Sardinia. Since 2001, 5 new cases have been observed: 4 members of the same family and 1 sporadic case. Therefore, since 1982 the total number of cases described in North Sardinia amounts to 18: 15 are familial (11 members of the same family group) and 3 sporadic. A short clinical description of the 5 new cases is reported.
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PMID:Epidemiology and clinical aspects of Werner's syndrome in North Sardinia: description of a cluster. 1747 82

Atherosclerotic cardiovascular disease is a life-threatening disorder. Cholesterol efflux from the cells is the rate-limiting step in regulating the intracellular cholesterol content as well as raft structure in the plasma membrane. The defect of cholesterol efflux leads to the development of atherosclerosis. Tangier disease (TD), a hereditary high-density lipoprotein deficiency, is characterized by the presence of defective cellular cholesterol efflux. Using the cDNA subtraction technique, we found that expression of Cdc42 was decreased markedly in fibroblasts and macrophages from patients with TD. Madin-Darby canine kidney cells expressing the dominant-negative form of Cdc42 had a reduced lipid efflux; inversely, cells expressing the active form had increased efflux. Furthermore, we found that cellular lipid efflux was defective and Cdc42 was reduced in fibroblasts from a premature aging disorder, Werner syndrome. Complementation experiments using an adenovirus carrying wild-type Cdc42 successfully corrected impaired lipid efflux in Werner syndrome cells. We concluded that Cdc42 may play important roles in cellular cholesterol efflux and that dysregulation of this type of RhoGTPase might lead to the development of atherosclerotic cardiovascular disease.
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PMID:Contribution of Cdc42 to cholesterol efflux in fibroblasts from Tangier disease and Werner syndrome. 1837 63

Werner syndrome (WS) is a rare autosomal recessive genetic instability/cancer predisposition disorder that displays many symptoms of premature aging. The mimicry of agerelated phenotypes in WS, as well as its dependence on a single defective gene product, has provided the impetus for studying this fascinating disease as a model system for normative aging and its related pathologies such as atherosclerosis, neoplasia, diabetes mellitus, and osteoporosis. The gene product defective in WS, WRN, is a member of the RecQ DNA helicase family that is widely distributed in all kingdoms of life, and is believed to play a central role in genomic stability by preferentially operating on non-canonical DNA structures. Although there have been considerable advances in our understanding of the biochemistry of WRN and its interacting protein partners, the in vivo molecular function(s) of WRN remain(s) elusive. In addition to summarizing the features and clinical progression of WS, the following chapter details our current understanding of the WRN protein with respect to its biochemistry and its interacting protein partners, and considers its putative in vivo roles in various DNA transactions.
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PMID:Werner Syndrome, aging and cancer. 1872 62


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