Telomerase gene mutations are associated with cirrhosis formation†‡§
Daniel Hartmann
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Surgery, Technical University Munich, Munich, Germany
These authors contributed equally.
Search for more papers by this authorUjala Srivastava
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Jackson Laboratory, Bar Harbor, Maine, USA
These authors contributed equally.
Search for more papers by this authorMichaela Thaler
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Internal Medicine I, University of Ulm, Ulm, Germany
Search for more papers by this authorKarin N. Kleinhans
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorGisèle N'Kontchou
Hôpital Jean Verdier, L'Assistance publique - Hôpitaux de Paris, Bondy Cedex, France
Search for more papers by this authorAnnika Scheffold
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorKerstin Bauer
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorRamona F. Kratzer
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorNatalia Kloos
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorSarah-Fee Katz
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorZhangfa Song
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorYvonne Begus-Nahrmann
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorAlexander Kleger
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Internal Medicine I, University of Ulm, Ulm, Germany
Search for more papers by this authorGuido von Figura
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Internal Medicine I, University of Ulm, Ulm, Germany
Search for more papers by this authorPavel Strnad
Department of Internal Medicine I, University of Ulm, Ulm, Germany
Search for more papers by this authorAndré Lechel
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorCagatay Günes
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorAndrej Potthoff
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorKatja Deterding
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorHeiner Wedemeyer
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorZhenyu Ju
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China
Search for more papers by this authorGe Song
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China
Search for more papers by this authorSonja Gillen
Department of Surgery, Technical University Munich, Munich, Germany
Search for more papers by this authorHubert Schrezenmeier
Institute for Clinical Transfusion Medicine and Immunogenetics, DRK Blood Donor Service Baden-Württemberg-Hesse and University of Ulm, Ulm, Germany
Search for more papers by this authorThomas Mertens
Institute of Virology, University Hospital Ulm, Ulm, Germany
Search for more papers by this authorMarianne Ziol
Hôpital Jean Verdier, L'Assistance publique - Hôpitaux de Paris, Bondy Cedex, France
Search for more papers by this authorHelmut Friess
Department of Surgery, Technical University Munich, Munich, Germany
Search for more papers by this authorMichael Jarek
Department of Genome Analysis, Helmholtz Centre for Infection Research, Braunschweig, Germany
Search for more papers by this authorMichael P. Manns
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorMichel Beaugrand
Hôpital Jean Verdier, L'Assistance publique - Hôpitaux de Paris, Bondy Cedex, France
Search for more papers by this authorCorresponding Author
K. Lenhard Rudolph
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
fax: 49-731-5036-1102
Institute of Molecular Medicine and Max-Planck-Research Group on Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany===Search for more papers by this authorDaniel Hartmann
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Surgery, Technical University Munich, Munich, Germany
These authors contributed equally.
Search for more papers by this authorUjala Srivastava
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Jackson Laboratory, Bar Harbor, Maine, USA
These authors contributed equally.
Search for more papers by this authorMichaela Thaler
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Internal Medicine I, University of Ulm, Ulm, Germany
Search for more papers by this authorKarin N. Kleinhans
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorGisèle N'Kontchou
Hôpital Jean Verdier, L'Assistance publique - Hôpitaux de Paris, Bondy Cedex, France
Search for more papers by this authorAnnika Scheffold
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorKerstin Bauer
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorRamona F. Kratzer
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorNatalia Kloos
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorSarah-Fee Katz
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorZhangfa Song
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorYvonne Begus-Nahrmann
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorAlexander Kleger
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Internal Medicine I, University of Ulm, Ulm, Germany
Search for more papers by this authorGuido von Figura
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Internal Medicine I, University of Ulm, Ulm, Germany
Search for more papers by this authorPavel Strnad
Department of Internal Medicine I, University of Ulm, Ulm, Germany
Search for more papers by this authorAndré Lechel
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorCagatay Günes
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Search for more papers by this authorAndrej Potthoff
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorKatja Deterding
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorHeiner Wedemeyer
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorZhenyu Ju
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China
Search for more papers by this authorGe Song
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China
Search for more papers by this authorSonja Gillen
Department of Surgery, Technical University Munich, Munich, Germany
Search for more papers by this authorHubert Schrezenmeier
Institute for Clinical Transfusion Medicine and Immunogenetics, DRK Blood Donor Service Baden-Württemberg-Hesse and University of Ulm, Ulm, Germany
Search for more papers by this authorThomas Mertens
Institute of Virology, University Hospital Ulm, Ulm, Germany
Search for more papers by this authorMarianne Ziol
Hôpital Jean Verdier, L'Assistance publique - Hôpitaux de Paris, Bondy Cedex, France
Search for more papers by this authorHelmut Friess
Department of Surgery, Technical University Munich, Munich, Germany
Search for more papers by this authorMichael Jarek
Department of Genome Analysis, Helmholtz Centre for Infection Research, Braunschweig, Germany
Search for more papers by this authorMichael P. Manns
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorMichel Beaugrand
Hôpital Jean Verdier, L'Assistance publique - Hôpitaux de Paris, Bondy Cedex, France
Search for more papers by this authorCorresponding Author
K. Lenhard Rudolph
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany
fax: 49-731-5036-1102
Institute of Molecular Medicine and Max-Planck-Research Group on Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany===Search for more papers by this authorPotential conflict of interest: Nothing to report.
Author Contributions: G.N., A.P., K.D., H.W., Z.J., G.S., F.X.,. S.G., H.S., M.Z., H.F., M.P.M., and M.B. recruited and managed patients in the study and were involved in data collection. D.H., U.S., S.F.K., Z.S., Y.B., A.K., G.F., P.S., and A.L. participated in sample preparation and data interpretation. D.H., U.S.; M.T., R.F.K., and Z.J. analyzed the sequencing data under the supervision of C.G., M.J., and K.L.R. D.H., U.S., K.N.K., A.S., K.B., R.F.K., N.K., C.G., and T.M. were involved in functional experiments. K.L.R. designed the experiments and wrote the first draft of the report. All authors were given the opportunity to comment on the drafts of the report and approved the final version before submission.
The funding organizations had no role in the design or conduct of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the article
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. Conclusion: 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. (HEPATOLOGY 2011;)
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| HEP_24217_sm_suppinfofig1-1.tif1.5 MB | Supporting Fig. 1. (A-F). Representative forward and reverse sequencing chromatograms from the indicated gene regions. The respective amino acid substitutions are indicated in the lines above the chromatograms: (A) wild-type TERT exon 1 (left side) and a patient with a heterozygous c.37C>A and c.40C>A variant (right side); (B) wild-type TERT exon 1 (left side) and an individual with a heterozygous c.193C>G variant (right side); (C) wild-type TERT exon 2 (left side) and a patient with a heterozygous c.1138C>T variant (right side); (D) wild-type TERT exon 2 (left side) and an individual with a heterozygous c.1336C>A variant (right side); (E) wild-type TERT exon 10 (left side) and a patient with a heterozygous c.2638G>T and c.2345 C>T variant (right side); (F) wild-type TERT exon 16 (left side) and an individual with a heterozygous c.3346G>C variant (right side); (G) wild-type TERT exon 16 (left side), a patient with a heterozygous c.3325G>A variant (middle), and a patient with a homozygous c.3325G>A variant (right side). The homozygous nature of the mutation is evident by the presence of a mutant allele sequence only while the heterozygous form shows both wild-type and mutant allele sequences. |
| HEP_24217_sm_suppinfofig1-2.tif2.2 MB | Supporting Information Figure 1-2 |
| HEP_24217_sm_suppinfofig2.tif1.5 MB | Supporting Fig. 2. The pie charts show the overall allele frequency (left sides) and the distribution (right side) of telomerase gene mutation in (A) cirrhosis patients and (B) non-cirrhotic controls. |
| HEP_24217_sm_suppinfofig3.tif1.1 MB | Supporting Fig. 3. The pie charts show the distribution of ethnicities of the complete study cohort (A) and mutation carriers (B). |
| HEP_24217_sm_suppinfotab1.doc59 KB | Supporting Table 1. Primers used for sequencing of indicated exons of TERT and of the TERC gene |
| HEP_24217_sm_suppinfotab2.doc33.5 KB | Supporting Table 2. Primers used to generate expression constructs for cirrhosis-associated TERT-mutations using site-directed mutagenesis |
| HEP_24217_sm_suppinfotab3.doc138.5 KB | Supporting Table 3. Distribution of hypomorphic telomerase reverse transcriptase variants in the study and control groups |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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