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Review
. 2017 Jan:33:105-114.
doi: 10.1016/j.arr.2016.03.002. Epub 2016 Mar 15.

Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions

Junko Oshima  1 , Julia M Sidorova  2 , Raymond J Monnat Jr  3
Affiliations
Review

Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions

Junko Oshima et al. Ageing Res Rev. 2017 Jan.

Abstract

Werner syndrome (WS) is a prototypical segmental progeroid syndrome characterized by multiple features consistent with accelerated aging. It is caused by null mutations of the WRN gene, which encodes a member of the RECQ family of DNA helicases. A unique feature of the WRN helicase is the presence of an exonuclease domain in its N-terminal region. Biochemical and cell biological studies during the past decade have demonstrated involvements of the WRN protein in multiple DNA transactions, including DNA repair, recombination, replication and transcription. A role of the WRN protein in telomere maintenance could explain many of the WS phenotypes. Recent discoveries of new progeroid loci found in atypical Werner cases continue to support the concept of genomic instability as a major mechanism of biological aging. Based on these biological insights, efforts are underway to develop therapeutic interventions for WS and related progeroid syndromes.

Keywords: Genomic instability; Human; Progeroid syndrome; Werner syndrome.

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Figures

Fig. 1
Fig. 1
Werner syndrome patient with homozygous null WRN mutations. Although apparently normal at age 8, cataracts were removed at age 36 and severe ankle ulcerations were recorded at age 56. (Registry# SANAN1010) (Hisama et al., 2006)
Fig. 2
Fig. 2
WRN disease mutations in classical WS patients. The rectangular box shows the WRN protein. Known functional domains are: exonuclease region (Exo), helicase region, RecQ C-terminus consensus region (RQC), helicase and RnaseD consensus region (HRDC) and the nuclear localization signal (NLS). Disease mutations are grouped based on the types of mutations. Splicing mutations that result in identical exon skipping are combined and indicated by the number of unique mutations as in (2). Splicing mutations that create new splice sites are indicated as “nss”. Modified from (Friedrich et al., 2010).
Fig. 3
Fig. 3
Model for the pathogenesis of WS. Modified from (Monnat, 2006). See text.
See this image and copyright information in PMC

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