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
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 progre...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
11 June 2015
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| In: |
Aging
Year: 2015, Jahrgang: 7, Heft: 11, Pages: 911-927 |
| ISSN: | 1945-4589 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694062/
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| Verfasserangaben: | Clemens Stockklausner, Simon Raffel, Julia Klermund, Obul Reddy Bandapalli, Fabian Beier, Tim H. Brümmendorf, Friederike Bürger, Sven W. Sauer, Georg F. Hoffmann, Holger Lorenz, Laura Tagliaferri, Daniel Nowak, Wolf-Karsten Hofmann, Rebecca Buergermeister, Carolin Kerber, Tobias Rausch, Jan O. Korbel, Brian Luke, Andreas Trumpp and Andreas E. Kulozik |
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| 245 | 1 | 2 | |a 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 |c Clemens Stockklausner, Simon Raffel, Julia Klermund, Obul Reddy Bandapalli, Fabian Beier, Tim H. Brümmendorf, Friederike Bürger, Sven W. Sauer, Georg F. Hoffmann, Holger Lorenz, Laura Tagliaferri, Daniel Nowak, Wolf-Karsten Hofmann, Rebecca Buergermeister, Carolin Kerber, Tobias Rausch, Jan O. Korbel, Brian Luke, Andreas Trumpp and Andreas E. Kulozik |
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| 520 | |a 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. | ||
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