Kudlow BA, Kennedy BK, Monnat RJ JrWerner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol 5:394-404

Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 06/2007; 8(5):394-404. DOI: 10.1038/nrm2161
Source: PubMed


Progeroid syndromes have been the focus of intense research in part because they might provide a window into the pathology of normal ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are two of the best characterized human progeroid diseases. Mutated genes that are associated with these syndromes have been identified, mouse models of disease have been developed, and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases.

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Available from: Brian K Kennedy, Sep 15, 2014
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    • "yndromes , and congenital lipodystrophies . Although pathophysiological mechanisms are still largely unknown , a num - ber of involved pathways recently came to attention . An important group of progeroid disorders are due to defective genomic main - tenance leading to loss of cells , cellular senescence and impaired replacement of damaged cells [ Kudlow et al . , 2007 ] . A second group of these diseases are associated with altered TGF - b signaling , which might play an important role in the pathogenesis since it is known to be involved in the induction of cellular senescence [ Passos et al . , 2010 ] . This group comprises cutis laxa syndromes and a progeroid variant of Marfan syndrome . This singu"
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    ABSTRACT: We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid-progeroid-lipodystrophy syndrome) and frameshift mutations at the 3’ end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.
    Full-text · Article · Apr 2014 · European journal of medical genetics
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    • "Most progeroid syndromes where the aetiological factors are known are monogenic and segmental, in that they show many, but not all, of the clinical characteristics of normal ageing. In those aspects where premature ageing occurs, the process and pathology are remarkably similar to that seen in normally aged individuals (Hofer et al. 2005; Kudlow et al. 2007). One of the more intensively studied progeroid syndromes is Werner (WS), with affected individuals showing premature onset of cataracts, skin atrophy, hair-greying and soft tissue calcification, together with age-related diseases such as type II diabetes, atherosclerosis and osteoporosis (Martin et al. 1999). "
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    ABSTRACT: Werner Syndrome (WS) is a human segmental progeria resulting from mutations in a DNA helicase. WS fibroblasts have a shortened replicative capacity, an aged appearance, and activated p38 MAPK, features that can be modulated by inhibition of the p38 pathway. Loss of the WRNp RecQ helicase has been shown to result in replicative stress, suggesting that a link between faulty DNA repair and stress-induced premature cellular senescence may lead to premature ageing in WS. Other progeroid syndromes that share overlapping pathophysiological features with WS also show defects in DNA processing, raising the possibility that faulty DNA repair, leading to replicative stress and premature cellular senescence, might be a more widespread feature of premature ageing syndromes. We therefore analysed replicative capacity, cellular morphology and p38 activation, and the effects of p38 inhibition, in fibroblasts from a range of progeroid syndromes. In general, populations of young fibroblasts from non-WS progeroid syndromes do not have a high level of cells with an enlarged morphology and F-actin stress fibres, unlike young WS cells, although this varies between strains. p38 activation and phosphorylated HSP27 levels generally correlate well with cellular morphology, and treatment with the p38 inhibitor SB203580 effects cellular morphology only in strains with enlarged cells and phosphorylated HSP27. For some syndromes fibroblast replicative capacity was within the normal range, whereas for others it was significantly shorter (e.g. HGPS and DKC). However, although in most cases SB203580 extended replicative capacity, with the exception of WS and DKC the magnitude of the effect was not significantly different from normal dermal fibroblasts. This suggests that stress-induced premature cellular senescence via p38 activation is restricted to a small subset of progeroid syndromes.
    Full-text · Article · Oct 2012 · Biogerontology
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    • "Genetically, WS patient cells show karyotypic abnormalities with DNA rearrangements including translocations and deletions (Fukuchi et al. 1989; Scappaticci et al. 1982). The human WRN protein is involved in many aspects of DNA metabolism including DNA repair (Bohr 2005), DNA replication (Pichierri et al. 2001; Rodriguez-Lopez et al. 2002; Sidorova et al. 2008) and DNA recombination (Saintigny et al. 2002, reviewed in Cox and Faragher 2007; Kudlow et al. 2007). The exonuclease activity of hWRN has been implicated in DNA repair using deletion mutants (Kashino et al. 2005), while single point mutations in either the exonuclease or helicase domain (or both) suggest separable but critical roles in recombination and cell survival (Swanson et al. 2004). "
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    ABSTRACT: Werner syndrome (WS) is a rare late-onset premature ageing disease showing many of the phenotypes associated with normal ageing, and provides one of the best models for investigating cellular pathways that lead to normal ageing. WS is caused by mutation of WRN, which encodes a multifunctional DNA replication and repair helicase/exonuclease. To investigate the role of WRN protein’s unique exonuclease domain, we have recently identified DmWRNexo, the fly orthologue of the exonuclease domain of human WRN. Here, we fully characterise DmWRNexo exonuclease activity in vitro, confirming 3′–5′ polarity, demonstrating a requirement for Mg2+, inhibition by ATP, and an ability to degrade both single-stranded DNA and duplex DNA substrates with 3′ or 5′ overhangs, or bubble structures, but with no activity on blunt ended DNA duplexes. We report a novel active site mutation that ablates enzyme activity. Lesional substrates containing uracil are partially cleaved by DmWRNexo, but the enzyme pauses on such substrates and is inhibited by abasic sites. These strong biochemical similarities to human WRN suggest that Drosophila can provide a valuable experimental system for analysing the importance of WRN exonuclease in cell and organismal ageing. Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9411-0) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2012 · Age
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