WRN mutations in Werner syndrome patients: Genomic rearrangements, unusual intronic mutations and ethnic-specific alterations

Center for Molecular Medicine Cologne, Institute of Human Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
Human Genetics (Impact Factor: 4.82). 07/2010; 128(1):103-11. DOI: 10.1007/s00439-010-0832-5
Source: PubMed


Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.

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    • "There was no evidence for a second mutation at the WRN locus. This alteration had been previously reported as a potential founder mutation; it was observed exclusively among Turkish patients with WS [Friedrich et al., 2010]. Both parents were also heterozygous for the c.3493C>T mutation. "
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    ABSTRACT: We describe a 28-year-old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma-like skin, spastic paraplegia, and apparent disability. The proband and each of his parents were heterozygous for a mutation in WRN, which could not explain his symptoms. Exome sequencing of the proband's blood DNA showed a homozygous c.626-1G > C mutation in intron 5 of the SAMHD1 gene, which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome. The RNA studies confirmed aberrant splicing of exon 6, and family studies showed that both parents are heterozygous for this mutation. We conclude that mutations in SAMHD1 - in addition to causing an early-onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome. The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2014; 164A(10). DOI:10.1002/ajmg.a.36664 · 2.16 Impact Factor
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    • "WRN is a multifunctional nuclear protein that maintains genome stability by means of DNA-dependent adenosine triphosphatase (ATPase), 3′→5′ helicase, 3′→5′ exonuclease, and DNA strand annealing activities.35 Most of the WRN mutations result in the production of truncated proteins lacking the nuclear localization signal, with the subsequent absence of functional WRN protein in nuclei.36 WRN has several functional domains and is considered to be a “caretaker of the genome” since it participates in distinct DNA metabolic pathways, including DNA replication, DNA recombination, telomere maintenance, apoptosis, and DNA repair.36 "
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    ABSTRACT: Hutchinson–Gilford Progeria Syndrome and Werner syndrome, also known as childhood- and adulthood-progeria, respectively, represent two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. The discovery of their genetic basis has led to the identification of several gene mutations leading to a spectrum of progeroid phenotypes ranging from moderate and mild–severe to very aggressive forms. In parallel, the creation of disease registers and databases provided available data for the design of relatively large-scale epidemiological studies, thereby allowing a better understanding of the nature and frequency of the premature aging-associated signs and symptoms. The aim of this article is to review the most recent findings concerning the epidemiology of premature aging disorders, their genetic basis, and the most recent reports on the frequency of associated diseases.
    Clinical Interventions in Aging 08/2013; 8:1023-1032. DOI:10.2147/CIA.S37213 · 2.08 Impact Factor
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    • "Segmental progeroid syndromes are a genetically heterogeneous collection of disorders whose presentations resemble accelerated aging (Martin, 1978). The best known example of an adult-onset segmental progeroid syndrome is the Werner syndrome (“Progeria of Adult”; WS), caused by mutations in the WRN gene (Yu et al., 1996; Friedrich et al., 2010). Our International Registry of Werner syndrome () has accumulated several dozen cases of “atypical” WS (AWS) – cases submitted by clinicians to us as examples of WS, but lack WRN mutations and have normal levels of the WRN protein. "
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    ABSTRACT: Segmental progeroid syndromes are groups of disorders with multiple features suggestive of accelerated aging. One subset of adult-onset progeroid syndromes, referred to as atypical Werner syndrome, is caused by mutations in the LMNA gene, which encodes a class of nuclear intermediate filaments, lamin A/C. We previously described rapid telomere attrition and accelerated replicative senescence in cultured fibroblasts overexpressing mutant lamin A. In this study, we investigated the cellular phenotypes associated with accelerated telomere shortening in LMNA mutant primary fibroblasts. In early passage primary fibroblasts with R133L or L140R LMNA mutations, shelterin protein components were already reduced while cells still retained telomere lengths comparable to those of controls. There was a significant inverse correlation between the degree of abnormal nuclear morphology and the level of TRF2, a shelterin subunit, suggesting a potential causal relationship. Stabilization of the telomeres via the introduction of the catalytic subunit of human telomerase, hTERT (human telomerase reverse transcriptase), did not prevent degradation of shelterin components, indicating that reduced TRF2 in LMNA mutants is not mediated by short telomeres. Interestingly, γ-H2AX foci (reflecting double strand DNA damage) in early passage LMNA mutant primary fibroblasts and LMNA mutant hTERT fibroblasts were markedly increased in non-telomeric regions of DNA. Our results raise the possibility that mutant lamin A/C causes global genomic instability with accumulation of non-telomeric DNA damage as an early event, followed by TRF2 degradation and telomere shortening.
    Frontiers in Genetics 07/2013; 4:129. DOI:10.3389/fgene.2013.00129
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