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Review
. 2014;60(3):239-46.
doi: 10.1159/000356030. Epub 2014 Jan 3.

Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome

Junko Oshima  1 , Fuki M Hisama
Affiliations
Review

Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome

Junko Oshima et al. Gerontology. 2014.

Abstract

Segmental progeroid syndromes are a group of disorders with multiple features resembling accelerated aging. Adult-onset Werner syndrome (WS) and childhood-onset Hutchinson-Gilford progeria syndrome are the best known examples. The discovery of genes responsible for such syndromes has facilitated our understanding of the basic mechanisms of aging as well as the pathogenesis of other common, age-related diseases. Our International Registry of Werner Syndrome accesses progeroid pedigrees from all over the world, including those for whom we have ruled out a mutation at the WRN locus. Cases without WRN mutations are operationally categorized as 'atypical WS' (AWS). In 2003, we identified LMNA mutations among a subset of AWS cases using a candidate gene approach. As of 2013, the Registry has 142 WS patients with WRN mutations, 11 AWS patients with LMNA mutations, and 49 AWS patients that have neither WRN nor LMNA mutations. Efforts are underway to identify the responsible genes for AWS with unknown genetic causes. While WS and AWS are rare disorders, the causative genes have been shown to have much wider implications for cancer, cardiovascular disease and the biology of aging. Remarkably, centenarian studies revealed WRN and LMNA polymorphic variants among those who have escaped various geriatric disorders.

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Figures

Figure 1
Figure 1
Map of the counties with reported Werner syndrome patients and atypical Werner syndrome cases referred to our Registry. WS patients with demonstrated WRN mutations have been identified in countries in green. Founder mutations have been are reported in Japan and Sardinia (red). Ethnic-specific mutations have been observed in Indian/Pakistani, Turk, Moroccan and Dutch WS patients (pink) [16]. AWS patients but not WS patients have been referred to the Registry from the countries in yellow.
Figure 2
Figure 2
Major DNA repair pathways in mammalian cells relevant to progeroid syndromes.
Figure 3
Figure 3
A Werner syndrome patient with homozygous null WRN mutations. Although apparently normal at ages 8, cataracts were removed at age 36 and severe ankle ulcerations were recorded at age 56 [33].
Figure 4
Figure 4
WRN disease mutations in classical WS patients. Rectangular box shows the WRN protein with N-terminus on the left and C-terminus on the right. Known functional domains include an exonuclease region (Exo), a helicase region, a RecQ C-terminus consensus region (RQC), a helicase domain, an RnaseD consensus region (HRDC), and a nuclear localization signal (NLS). Mutations are grouped based on the types of mutations: missense, stop codon, insertion/deletion or splicing mutation. Arrows indicate the location of the mutations and the amino acid changes caused by the mutations. Splicing mutations are indicated by the affected exons. Deep intron mutations that create new exons are indicated as “Ins” along with the flanking exons. Splice mutations that result in the use of alternative splice sites (“alt”) are indicated as such. Genomic rearrangements, either deletion (Del) or duplication (Dup) are shown at corresponding protein locations, with regions extending beyond this figure in dotted lines [16].
Figure 5
Figure 5
LMNA mutations in AWS. The diagram shows the structure of lamin A. It consists of globular head domain, linker regions, α-helical coiled coil domain and globular tail domain. Heterozygous amino acid changes seen in AWS are also shown. Left photo shows a 36 year-old AWS patient with L140R mutation who has cataracts, osteoporosis and an aged-appearance Right photo shows a 37 year-old man with an exon 11 splicing mutation who had multiple episodes of myocardial infarction and whose facial appearance suggests precocious aging [34].
See this image and copyright information in PMC

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References

    1. Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD. Positional cloning of the Werner's syndrome gene. Science. 1996;272:258–262. - PubMed
    1. Oshima J, Martin GM, Hisama FM. Werner syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. Genereviews. Seattle (WA): 2013.
    1. Imura H, Nakao Y, Kuzuya H, Okamoto M, Okamoto M, Yamada K. Clinical, endocrine and metabolic aspects of the werner syndrome compared with those of normal aging. Adv Exp Med Biol. 1985;190:171–185. - PubMed
    1. Martin GM, Oshima J. Lessons from human progeroid syndromes. Nature. 2000;408:263–266. - PubMed
    1. Gorbunova V, Seluanov A, Mao Z, Hine C. Changes in DNA repair during aging. Nucleic Acids Res. 2007;35:7466–7474. - PMC - PubMed

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