Send to

Choose Destination
Aging (Albany NY). 2015 Nov;7(11):911-27.

A novel autosomal recessive TERT T1129P mutation in a dyskeratosis congenita family leads to cellular senescence and loss of CD34+ hematopoietic stem cells not reversible by mTOR-inhibition.

Author information

Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty of the RWTH Aachen University, 52062 Aachen, Germany.
Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
European Molecular Biology Laboratory (EMBL), Genomics Core Facility, D 69117 Heidelberg, Germany.
European Molecular Biology Laboratory (EMBL), Genome Biology Unit and Molecular Medicine Partnership Unit, D 69117 Heidelberg, Germany.
Institute of Molecular Biology gGmbH, gefördert durch die Böhringer Ingelheim Stiftung, 55128 Mainz, Germany.


The TERT gene encodes for the reverse transcriptase activity of the telomerase complex and mutations in TERT can lead to dysfunctional telomerase activity resulting in diseases such as dyskeratosis congenita (DKC). Here, we describe a novel TERT mutation at position T1129P leading to DKC with progressive bone marrow (BM) failure in homozygous members of a consanguineous family. BM hematopoietic stem cells (HSCs) of an affected family member were 300-fold reduced associated with a significantly impaired colony forming capacity in vitro and impaired repopulation activity in mouse xenografts. Recent data in yeast suggested improved cellular checkpoint controls by mTOR inhibition preventing cells with short telomeres or DNA damage from dividing. To evaluate a potential therapeutic option for the patient, we treated her primary skin fibroblasts and BM HSCs with the mTOR inhibitor rapamycin. This led to prolonged survival and decreased levels of senescence in T1129P mutant fibroblasts. In contrast, the impaired HSC function could not be improved by mTOR inhibition, as colony forming capacity and multilineage engraftment potential in xenotransplanted mice remained severely impaired. Thus, rapamycin treatment did not rescue the compromised stem cell function of TERTT1129P mutant patient HSCs and outlines limitations of a potential DKC therapy based on rapamycin.


TERC; TERT; mTOR; rapamycin; senescence; sirolimus

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center