Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions

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.

Ageing as an Important Risk Factor for Cancer

“…Diseases such as xeroderma pigmentosum, Werner syndrome, Lynch syndrome and Fanconi anemia can be considered paradigmatic examples. Association of these rare diseases with untimely occurring malignant tumors was the leading motif in their initial clinical description (30,(46)(47)(48)(49)(50).…”

The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation

“…WRN is a RecQ helicase that is thought to preserve genome integrity, at least in part by maintaining telomere length homeostasis (50). Our study provides a mechanistic explanation for the loss of telomeres replicated by lagging-strand synthesis in WRNdeficient cells.…”

Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent <i>de novo</i> mutation in the <i>POLD1</i> gene

“…Although roles of some of the affected genes (PPARγ, PLIN1, CIDEC, and AKT2) have been established in adipose tissue differentiation or function, insulin signaling and lipid metabolism, the molecular mechanisms underlying selective fat loss remain to be resolved. MDPL syndrome and MAD belong to similar groups as syndromes characterized by premature aging and inheritable envelope and/or DNA repair defects [2,4,25]. MDPL syndrome shows a spectrum of clinical features that have overlapping manifestations and variable expression in the development stage of the phenotype as shown in Table 3.…”

“…It plays a critical role in genome maintenance through its involvement in replicative DNA synthesis and multiple synthetic repair processes [27,28]. POLD1 cooperates with WRN, which a gene that is typically associated with Werner syndrome [25,29]. Moreover, the age-related decrease in POLD1 expression has been shown to be involved in the DNA repair pathway in vitro [29][30][31].…”

“…Her phenotypic features excluding MAD [8,9] did not fit any of those of CPLD [1,3] such as unique adipose tissue topography, or the criteria for classical Werner syndrome, including the cardinal signs and symptoms of juvenile cataracts, Achilles tendon calcification, and bone deformation [23][24][25].…”