title: Telomerase gene mutations are associated with cirrhosis formation.
abstract: Telomere shortening impairs liver regeneration in mice and is associated with cirrhosis formation in humans with chronic liver disease. In humans, telomerase mutations have been associated with familial diseases leading to bone marrow failure or lung fibrosis. It is currently unknown whether telomerase mutations associate with cirrhosis induced by chronic liver disease. The telomerase RNA component (TERC) and the telomerase reverse transcriptase (TERT) were sequenced in 1,121 individuals (521 patients with cirrhosis induced by chronic liver disease and 600 noncirrhosis controls). Telomere length was analyzed in patients carrying telomerase gene mutations. Functional defects of telomerase gene mutations were investigated in primary human fibroblasts and patient-derived lymphocytes. An increased incidence of telomerase mutations was detected in cirrhosis patients (allele frequency 0.017) compared to noncirrhosis controls (0.003, P value 0.0007; relative risk [RR] 1.859; 95% confidence interval [CI] 1.552-2.227). Cirrhosis patients with TERT mutations showed shortened telomeres in white blood cells compared to control patients. Cirrhosis-associated telomerase mutations led to reduced telomerase activity and defects in maintaining telomere length and the replicative potential of primary cells in culture.
  
  
  CONCLUSIONS
  This study provides the first experimental evidence that telomerase gene mutations are present in patients developing cirrhosis as a consequence of chronic liver disease. These data support the concept that telomere shortening can represent a causal factor impairing liver regeneration and accelerating cirrhosis formation in response to chronic liver disease.
authors.affiliation: Department on Stem Cell Aging, University of Ulm, Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartmann
authors.forename: Ujala
authors.initials: U
authors.lastname: Srivastava
authors.forename: Michaela
authors.initials: M
authors.lastname: Thaler
authors.forename: Karin N
authors.initials: KN
authors.lastname: Kleinhans
authors.forename: Gisèle
authors.initials: G
authors.lastname: N'kontchou
authors.forename: Annika
authors.initials: A
authors.lastname: Scheffold
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bauer
authors.forename: Ramona F
authors.initials: RF
authors.lastname: Kratzer
authors.forename: Natalia
authors.initials: N
authors.lastname: Kloos
authors.forename: Sarah-Fee
authors.initials: SF
authors.lastname: Katz
authors.forename: Zhangfa
authors.initials: Z
authors.lastname: Song
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Begus-Nahrmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleger
authors.forename: Guido
authors.initials: G
authors.lastname: von Figura
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.forename: Cagatay
authors.initials: C
authors.lastname: Günes
authors.forename: Andrej
authors.initials: A
authors.lastname: Potthoff
authors.forename: Katja
authors.initials: K
authors.lastname: Deterding
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.forename: Ge
authors.initials: G
authors.lastname: Song
authors.forename: Feng
authors.initials: F
authors.lastname: Xiao
authors.forename: Sonja
authors.initials: S
authors.lastname: Gillen
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.forename: Thomas
authors.initials: T
authors.lastname: Mertens
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Michael
authors.initials: M
authors.lastname: Jarek
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Michel
authors.initials: M
authors.lastname: Beaugrand
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics*; D008107:Liver Diseases / Q000150:complications; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019098:Telomerase / Q000235:genetics*
chemical_list: D019098:Telomerase