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Werner Syndrome (werner + syndrome)

Distribution by Scientific Domains

Medical Sciences	50%
Life Sciences	50%

Selected Abstracts

Primary lung cancer associated with Werner syndrome

GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 4 2010
Shunichiro Ohnishi
A 52-year-old man with Werner Syndrome (WS) was admitted to our hospital for the treatment of skin ulcers on his thighs. Routine chest radiography revealed an abnormal shadow in the left upper lung field. Computed tomography (CT) revealed a poorly demarcated homogeneous mass (diameter, 4 cm) in the S1 + 2 lung area; no pleural effusion was observed. CT-guided percutaneous needle biopsy revealed the presence of an adenocarcinoma. Other imaging studies did not reveal any lymph-node involvement or presence of metastatic lesions. The patient was diagnosed with stage IB adenocarcinoma (T2N0M0), and a left upper lobectomy was successfully carried out; postoperative wound healing was steady and uneventful, with no obvious ulcer formation. Primary lung cancers very rarely develop in patients with WS; non-epithelial tumors are usually observed in such patients. Patients with WS usually develop severe skin problems, such as refractory skin ulcers in the extremities; however, our patient did not develop any skin-related complications after surgery. As the expected lifespan of patients with WS is increasing, we need to pay attention not only to the rare non-epithelial malignancy, but also cancer. Further, the expected short lifespan of patients with WS, as well as the possibility of skin-related problems after surgery, should not be considered while deciding whether to take the option of surgery in the case of malignancy. Geriatr Gerontol Int 2010; 10: 319,323. [source]

DNA repair and mutagenesis in Werner syndrome ,

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2-3 2001
Vilhelm A. Bohr
Abstract Werner syndrome (WS) is the hallmark premature aging syndrome in which the patients appear much older than their actual chronological age. The disorder is associated with significantly increased genome instability and with transcriptional deficiencies. There has been some uncertainty about whether WS cells are defective in DNA repair. We thus examined repair in vitro in nuclear and mitochondrial DNA. Whereas cellular studies so far do not show significant DNA repair deficiencies, biochemical studies with the Werner protein clearly indicate that it plays a role in DNA repair. Environ. Mol. Mutagen. 38:227,234, 2001. Published 2001 Wiley-Liss, Inc. [source]

Primary lung cancer associated with Werner syndrome

Impaired efflux of cholesterol from aged cells and its molecular mechanism: A basis for age-related enhancement of atherosclerosis

GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2007
Shizuya Yamashita
Aging is one of the risk factors for atherosclerotic cardiovascular diseases, however, its molecular mechanism is currently unknown. Many types of cells in the atherosclerotic lesions are considered to have various biological abnormalities such as impaired lipid homeostasis and slow cell proliferation, which may be related to senescence at cellular levels. One of the common characteristics of senescent cells in vitro is the alteration of actin cytoskeletons, which were reported to be involved in the intracellular transport of lipids. Cholesterol efflux from the cells is the initial step of reverse cholesterol transport, a major protective system against atherosclerosis. Recently, we demonstrated that Cdc42, a member of the Rho -GTPase family, might be crucial for cellular lipid transport and cholesterol efflux based upon studies of Tangier cells that are deficient in ABCA1 gene. In the current review, we also indicate that the expression of Cdc42 is decreased in the cells from aged subjects in close association with the retarded intracellular lipid transport. Furthermore, the Cdc42 expression is reduced by culturing fibroblasts in vitro for a long duration. Werner syndrome (WS) is characterized by the early onset of senescent phenotypes including premature atherosclerotic cardiovascular diseases, although the underlying molecular mechanism for the enhanced atherosclerosis has not been fully understood yet. We examined the intracellular lipid transport and cholesterol efflux and the expression levels of cholesterol efflux-related molecules in skin fibroblasts obtained from patients with WS. Cholesterol efflux was markedly reduced in the WS fibroblasts in association with an increased cellular cholesterol content. Fluorescent recovery after photobleaching technique revealed that intracellular lipid transport around Golgi apparatus was markedly reduced when using a C6-NBD-ceramide as a tracer. Cdc42 protein and its guanosine 5,-triphosphate-bound active form were markedly reduced in the WS fibroblasts. The adenovirus-mediated complementation of wild-type Cdc42 corrected the impaired cholesterol efflux, intracellular lipid transport and cellular cholesterol levels in the WS fibroblasts. These data indicate that the reduced expression of Cdc42 might be responsible for the abnormal lipid transport, which in turn might be related to the accelerated cardiovascular manifestations in WS patients. The current review focuses on the impaired efflux of cholesterol from aged cells and its molecular mechanism as a basis for age-related enhancement of atherosclerosis. [source]

A role for the Werner syndrome protein in epigenetic inactivation of the pluripotency factor Oct4

AGING CELL, Issue 4 2010
Johanna A. Smith
Summary Werner syndrome (WS) is an autosomal recessive disorder, the hallmarks of which are premature aging and early onset of neoplastic diseases (Orren, 2006; Bohr, 2008). The gene, whose mutation underlies the WS phenotype, is called WRN. The protein encoded by the WRN gene, WRNp, has DNA helicase activity (Gray et al., 1997; Orren, 2006; Bohr, 2008; Opresko, 2008). Extensive evidence suggests that WRNp plays a role in DNA replication and DNA repair (Chen et al., 2003; Hickson, 2003; Orren, 2006; Turaga et al., 2007; Bohr, 2008). However, WRNp function is not yet fully understood. In this study, we show that WRNp is involved in de novo DNA methylation of the promoter of the Oct4 gene, which encodes a crucial stem cell transcription factor. We demonstrate that WRNp localizes to the Oct4 promoter during retinoic acid-induced differentiation of human pluripotent cells and associates with the de novo methyltransferase Dnmt3b in the chromatin of differentiating pluripotent cells. Depletion of WRNp does not affect demethylation of lysine 4 of the histone H3 at the Oct4 promoter, nor methylation of lysine 9 of H3, but it blocks the recruitment of Dnmt3b to the promoter and results in the reduced methylation of CpG sites within the Oct4 promoter. The lack of DNA methylation was associated with continued, albeit greatly reduced, Oct4 expression in WRN-deficient, retinoic acid-treated cells, which resulted in attenuated differentiation. The presented results reveal a novel function of WRNp and demonstrate that WRNp controls a key step in pluripotent stem cell differentiation. [source]

Delayed kinetics of DNA double-strand break processing in normal and pathological aging

AGING CELL, Issue 1 2008
Olga A. Sedelnikova
Summary Accumulation of DNA damage may play an essential role in both cellular senescence and organismal aging. The ability of cells to sense and repair DNA damage declines with age. However, the underlying molecular mechanism for this age-dependent decline is still elusive. To understand quantitative and qualitative changes in the DNA damage response during human aging, DNA damage-induced foci of phosphorylated histone H2AX (,-H2AX), which occurs specifically at sites of DNA double-strand breaks (DSBs) and eroded telomeres, were examined in human young and senescing fibroblasts, and in lymphocytes of peripheral blood. Here, we show that the incidence of endogenous ,-H2AX foci increases with age. Fibroblasts taken from patients with Werner syndrome, a disorder associated with premature aging, genomic instability and increased incidence of cancer, exhibited considerably higher incidence of ,-H2AX foci than those taken from normal donors of comparable age. Further increases in ,-H2AX focal incidence occurred in culture as both normal and Werner syndrome fibroblasts progressed toward senescence. The rates of recruitment of DSB repair proteins to ,-H2AX foci correlated inversely with age for both normal and Werner syndrome donors, perhaps due in part to the slower growth of ,-H2AX foci in older donors. Because genomic stability may depend on the efficient processing of DSBs, and hence the rapid formation of ,-H2AX foci and the rapid accumulation of DSB repair proteins on these foci at sites of nascent DSBs, our findings suggest that decreasing efficiency in these processes may contribute to genome instability associated with normal and pathological aging. [source]

WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair

AGING CELL, Issue 4 2003
Lishan Chen
Summary Werner syndrome (WS) predisposes patients to cancer and premature aging, owing to mutations in WRN. The WRN protein is a RECQ-like helicase and is thought to participate in DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) or homologous recombination (HR). It has been previously shown that non-homologous DNA ends develop extensive deletions during repair in WS cells, and that this WS phenotype was complemented by wild-type (wt) WRN. WRN possesses both 3, , 5, exonuclease and 3, , 5, helicase activities. To determine the relative contributions of each of these distinct enzymatic activities to DSB repair, we examined NHEJ and HR in WS cells (WRN,/,) complemented with either wtWRN, exonuclease-defective WRN (E,), helicase-defective WRN (H,) or exonuclease/helicase-defective WRN (E,H,). The single E, and H, mutants each partially complemented the NHEJ abnormality of WRN,/, cells. Strikingly, the E,H, double mutant complemented the WS deficiency nearly as efficiently as did wtWRN. Similarly, the double mutant complemented the moderate HR deficiency of WS cells nearly as well as did wtWRN, whereas the E, and H, single mutants increased HR to levels higher than those restored by either E,H, or wtWRN. These results suggest that balanced exonuclease and helicase activities of WRN are required for optimal HR. Moreover, WRN appears to play a structural role, independent of its enzymatic activities, in optimizing HR and efficient NHEJ repair. Another human RECQ helicase, BLM, suppressed HR but had little or no effect on NHEJ, suggesting that mammalian RECQ helicases have distinct functions that can finely regulate recombination events. [source]

REVIEW: Plasminogen Activator Inhibitor-1 (PAI-1): A Key Factor Linking Fibrinolysis and Age-Related Subclinical and Clinical Conditions

CARDIOVASCULAR THERAPEUTICS, Issue 5 2010
Matteo Cesari
SUMMARY Introduction: The close relationship existing between aging and thrombosis has growingly been studied in this last decade. The age-related development of a prothrombotic imbalance in the fibrinolysis homeostasis has been hypothesized as the basis of this increased cardiovascular and cerebrovascular risk. Fibrinolysis is the result of the interactions among multiple plasminogen activators and inhibitors constituting the enzymatic cascade, and ultimately leading to the degradation of fibrin. The plasminogen activator system plays a key role in a wide range of physiological and pathological processes. Methods: Narrative review. Results: Plasminogen activator inhibitor-1 (PAI-1) is a member of the superfamily of serine-protease inhibitors (or serpins), and the principal inhibitor of both the tissue-type and the urokinase-type plasminogen activator, the two plasminogen activators able to activate plasminogen. Current evidence describing the central role played by PAI-1 in a number of age-related subclinical (i.e., inflammation, atherosclerosis, insulin resistance) and clinical (i.e., obesity, comorbidities, Werner syndrome) conditions is presented. Conclusions: Despite some controversial and unclear issues, PAI-1 represents an extremely promising marker that may become a biological parameter to be progressively considered in the prognostic evaluation, in the disease monitoring, and as treatment target of age-related conditions in the future. [source]

A novel mutation of the WRN gene in a Chinese patient with Werner syndrome

CLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 3 2008
N. Zhao
Summary Werner syndrome (WS) is an autosomal recessive inherited disease characterized by features of premature ageing. It is caused by mutations of the WRN gene encoding a protein with both exonuclease and helicase activities. The aim of this study was to identify gene mutations in a Chinese patient with WS. A 31-year-old Chinese man with typical features of WS was diagnosed as having probable WS. We performed PCR to scan 33 exons of the WRN gene of the patient, six members of his family, and 50 unrelated controls. Automated DNA sequencing identified the mutation in the patient as 3250delG. The proband's parents, son, younger brother and paternal grandmother were heterozygous. We did not find this heterozygous mutation in the proband's maternal grandmother or in any of 50 normal controls. The novel mutation in the WRN gene is responsible for the pathogenesis of WS and genetic detection is a useful method to confirm the diagnosis. [source]