Werner syndrome (i.e., adult progeria) is a rare autosomal recessive disorder caused by mutations of the WRN gene, which is characterized by the premature appearance of features associated with normal aging and cancer predisposition.
Human WRN, a RecQ helicase encoded by the Werner syndrome gene, is implicated in genome maintenance, including replication, recombination, excision repair and DNA damage response.
Our results identify the human WRN RECQ protein as a G4 helicase that modulates gene expression in G4-dependent fashion at many chromosomal sites and provide several new and unexpected mechanistic insights into WS disease pathogenesis.
Functional mutations in WRN cause Werner syndrome, a human autosomal recessive disease characterized by premature aging and associated with genetic instability and increased cancer risk.
Telomeric abnormalities caused by loss of function of the RecQ helicase WRN are linked to the multiple premature ageing phenotypes that characterize Werner syndrome.
Inactivating mutations in RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types.
Thus, immunohistochemical detection of WRN in erythroblasts from bone marrow paraffin sections could be useful in screening of WS cases and worthy of further molecular confirmation.
Thus, the majority of wide and complex pathological phenotypes of WS may be explained in a unified manner by the cascade beginning with telomere dysfunction initiated by WRN gene mutation.
In the acquired forms, genes such as LMNA, PPARG, CIDEC (cell-death-inducing DNA fragmentation factor a-like effector c) and PLIN1 are heavily involved in familial partial lipodystrophy (FPLD) type 2 (also known as the Dunnigan-Variety) and WRN along with RECQL5 in Werner Syndrome (WS).
After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency.
Mutations in the RecQ helicases BLM and WRN are linked to the cancer-prone disorder Bloom's syndrome and premature aging condition Werner syndrome, respectively.
We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeriaWerner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase.
Interestingly, a WRN cDNA expression vector bearing a valine at position 114 instead of isoleucine significantly affected cholesterol efflux in WS fibroblasts.
Although WS has been characterized by a variety of clinical manifestations mimicking premature aging, the recent longevity and delayed age-associated manifestations observed both from Japanese WS and general population may suggest a common environmental effect on some gene(s) other than WRN and may give us a newer pathophysiological look at WS and also natural aging through the molecular dysfunction of WRN.