Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population.
ABSTRACT The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus (NIDDM), ocular cataracts and osteoporosis [Epstein et al., 1966]. The major cause of death (at a median age of 47) is myocardial infarction (MI) [Epstein et al., 1966]. The WS mutation involves a member (WRN) of the RecQ family of helicases and may perturb DNA replication, repair, recombination, transcription, or chromosomal segregation [Yu et al., 1996]. We now report data on 149 MI cases and age-matched controls suggesting that a polymorphic WRN variant is associated with increased risk for MI. Based on our data, homozygosity for a cysteine at amino acid 1367 (the most prevalent genotype) predicts a 2.78 times greater risk of MI (95% confidence intervals: 1.23 to 6.86). The variant was not significantly associated with NIDDM. The two alleles (cysteine vs. arginine) could influence helicase activity, turnover, macromolecular interactions or, alternatively, could be markers for haplotypes influencing WRN regulation or reflecting gene action at linked loci. However, given the caveats implicit in genetic association studies, it is imperative that the present results be replicated in independent populations.
SourceAvailable from: George M. Martin
Article: Molecular Basis of Progeroid Syndrome Molecular Basis of Progeroid Syndrome Molecular Basis of Progeroid Syndrome Molecular Basis of Progeroid Syndrome Molecular Basis of Progeroid Syndromes– s– s– s– s– the W the W the W the W the Werner and erner and erner and erner and erner and Hutchinson-Gilford Syndromes Hutchinson-Gilford Syndromes Hutchinson-Gilford Syndromes Hutchinson-Gilford Syndromes Hutchinson-Gilford Syndromes[Show abstract] [Hide abstract]
ABSTRACT: Segmental progeroid syndromes are members of a group of disorders in which affected individuals present various features suggestive of accelerated aging. The two best-known examples are the Werner syndrome (WS; "Progeria of the adult") and the Hutchinson-Gilford Progeria syndrome (HGPS; "Progeria of child-hood"). The gene responsible for WS, W R N, was identified in 1996 and encodes a multifunctional nuclear protein with exonuclease and helicase domains. WS patients and cells isolated from the WS patients show various genomic instability phenotypes, including an increased incidence of cancer. The WRN protein is thought to play a crucial role in optimizing the regulation of DNA repair processes. Recently, a novel recurrent mutation in the L M N A gene has been shown to be responsible for HGPS. L M N A encodes nuclear intermediate filaments, lamins A and C; mutant lamins are thought to result in nuclear fragility. There are at least six other disorders caused by L M N A mutations, most of which affect cells and tissues of mesenchymal origins, including atypical forms of WS. The pathophysiologies of these and certain other progeroid syndromes indicate an important role for DNA damage in the genesis of common age-related disorders.
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ABSTRACT: 4-Hydroxy-2-nonenal (HNE) is a reactive α,β-unsaturated aldehyde generated during oxidative stress and subsequent peroxidation of polyunsaturated fatty acids. Here, Werner protein (WRN) was identified as a novel target for modification by HNE. Werner syndrome arises through mutations in the WRN gene that encodes the RecQ DNA helicase which is critical for maintaining genomic stability. This hereditary disease is associated with chromosomal instability, premature aging and cancer predisposition. WRN appears to participate in the cellular response to oxidative stress and cells devoid of WRN display elevated levels of oxidative DNA damage. We demonstrated that helicase/ATPase and exonuclease activities of HNE-modified WRN protein were inhibited both in vitro and in immunocomplexes purified from the cell extracts. Sites of HNE adduction in human WRN were identified at Lys577, Cys727, His1290, Cys1367, Lys1371 and Lys1389. We applied in silico modeling of the helicase and RQC domains of WRN protein with HNE adducted to Lys577 and Cys727 and provided a potential mechanism of the observed deregulation of the protein catalytic activities. In light of the obtained results, we postulate that HNE adduction to WRN is a post-translational modification, which may affect WRN conformational stability and function, contributing to features and diseases associated with premature senescence.Nucleic Acids Research 08/2014; 42(17). DOI:10.1093/nar/gku783 · 8.81 Impact Factor
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ABSTRACT: Werner syndrome is a rare autosomal recessive disorder caused by mutations in the human WRN gene and characterized by the early onset of normal aging symptoms. Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. A genetic association study of eight non-synonymous polymorphisms in the WRN gene and the incidence of femoral fracture was undertaken in 1,632 consecutive Japanese autopsies in which 140 patients had experienced the fracture during their lifetime. The results were validated in 251 unrelated postmenopausal Japanese women with osteoporosis and 269 non-institutionalized, community-dwelling Japanese adults. A statistically significant association was observed between rs2230009 (c.340G > A)-which results in a Val to Ile substitution-and fracture risk; the incidence of femoral fracture increased dose-dependently with the number of A alleles (p = 0.0120). Femoral neck bone and whole bone densities were lower among postmenopausal women with osteoporosis and community-dwelling adults, respectively, if they were of the AG instead of the GG genotype. The results suggest that Japanese subjects bearing at least one A allele of rs2230009 of the WRN gene are at a significantly higher risk of femoral fracture, possibly due to decreased bone density.Journal of Bone and Mineral Metabolism 01/2015; DOI:10.1007/s00774-014-0636-0 · 2.11 Impact Factor