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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2332-2339. Prepublished online as a Blood First Edition Paper on November 18, 2004; DOI 10.1182/blood-2004-09-3659. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-09-3659v1 105/6/2332    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ly, H. Articles by Parslow, T. G. Search for Related Content PubMed PubMed Citation Articles by Ly, H. Articles by Parslow, T. G. Related Collections Hematopoiesis and Stem Cells Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Functional characterization of telomerase RNA variants found in patients with hematologic disorders Hinh Ly, Rodrigo T. Calado, Paulette Allard, Gabriela M. Baerlocher, Peter M. Lansdorp, Neal S. Young, and Tristram G. Parslow From the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; the National Heart, Lung, and Blood Institute, Hematology Branch, Bethesda, MD; and the Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada. Human telomerase uses a specific cellular RNA, called hTERC, as the template to synthesize telomere repeats at chromosome ends. Approximately 10% to 15% of patients with aplastic anemia or other bone marrow failure syndromes are carriers of hTERC sequence variants whose functional significance, in most cases, is unknown. We screened 10 reported and 2 newly discovered hTERC variants from such patients and found that 10 of these negatively affected telomerase enzymatic function when they were used to reconstitute telomerase enzymatic function in human cells. Most functional deficits were due to perturbations of hTERC secondary structure and correlated well with the degrees of telomere shortening and reduced telomerase activity observed in peripheral blood lymphocytes of the representative patients. We also found no evidence of dominant-negative activity in any of the mutants. Therefore, loss of telomerase activity and of telomere maintenance resulting from inherited hTERC mutations may limit marrow stem cell renewal and predispose some patients to bone marrow failure. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. T. Calado, W. T. Yewdell, K. L. Wilkerson, J. A. Regal, S. Kajigaya, C. A. Stratakis, and N. S. Young Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells Blood, September 10, 2009; 114(11): 2236 - 2243. [Abstract] [Full Text] [PDF] S. Chakraborty, C.-L. Sun, L. Francisco, M. Sabado, L. Li, K. L. Chang, S. Forman, S. Bhatia, and R. Bhatia Accelerated Telomere Shortening Precedes Development of Therapy-Related Myelodysplasia or Acute Myelogenous Leukemia After Autologous Transplantation for Lymphoma J. Clin. Oncol., February 10, 2009; 27(5): 791 - 798. [Abstract] [Full Text] [PDF] C. Trahan and F. Dragon Dyskeratosis congenita mutations in the H/ACA domain of human telomerase RNA affect its assembly into a pre-RNP RNA, February 1, 2009; 15(2): 235 - 243. [Abstract] [Full Text] [PDF] R. T. Calado, J. A. Regal, M. Hills, W. T. Yewdell, L. F. Dalmazzo, M. A. Zago, P. M. Lansdorp, D. Hogge, S. J. Chanock, E. H. Estey, et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia PNAS, January 27, 2009; 106(4): 1187 - 1192. [Abstract] [Full Text] [PDF] R. T. Calado and N. S. Young Telomere maintenance and human bone marrow failure Blood, May 1, 2008; 111(9): 4446 - 4455. [Abstract] [Full Text] [PDF] F. D. Goldman, G. Aubert, A. J. Klingelhutz, M. Hills, S. R. Cooper, W. S. Hamilton, A. J. Schlueter, K. Lambie, C. J. Eaves, and P. M. Lansdorp Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita Blood, May 1, 2008; 111(9): 4523 - 4531. [Abstract] [Full Text] [PDF] G. Aubert and P. M. Lansdorp Telomeres and Aging Physiol Rev, April 1, 2008; 88(2): 557 - 579. [Abstract] [Full Text] [PDF] M. Xie, A. Mosig, X. Qi, Y. Li, P. F. Stadler, and J. J.-L. Chen Structure and Function of the Smallest Vertebrate Telomerase RNA from Teleost Fish J. Biol. Chem., January 25, 2008; 283(4): 2049 - 2059. [Abstract] [Full Text] [PDF] A. Marrone, A. Walne, H. Tamary, Y. Masunari, M. Kirwan, R. Beswick, T. Vulliamy, and I. Dokal Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome Blood, December 15, 2007; 110(13): 4198 - 4205. [Abstract] [Full Text] [PDF] C. K. Garcia, W. E. Wright, and J. W. Shay Human diseases of telomerase dysfunction: insights into tissue aging Nucleic Acids Res., December 3, 2007; 35(22): 7406 - 7416. [Abstract] [Full Text] [PDF] A. Marrone, P. Sokhal, A. Walne, R. Beswick, M. Kirwan, S. Killick, M. Williams, J. Marsh, T. Vulliamy, and I. Dokal Functional characterization of novel telomerase RNA (TERC) mutations in patients with diverse clinical and pathological presentations Haematologica, August 1, 2007; 92(8): 1013 - 1020. [Abstract] [Full Text] [PDF] X. Li, H. Nishizuka, K. Tsutsumi, Y. Imai, Y. Kurihara, and S. Uesugi Structure, Interactions and Effects on Activity of the 5'-terminal Region of Human telomerase RNA J. 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Yamaguchi, R. T. Calado, H. Ly, S. Kajigaya, G. M. Baerlocher, S. J. Chanock, P. M. Lansdorp, and N. S. Young Mutations in TERT, the Gene for Telomerase Reverse Transcriptase, in Aplastic Anemia N. Engl. J. Med., April 7, 2005; 352(14): 1413 - 1424. [Abstract] [Full Text] [PDF] M. ARMANIOS and C.W. GREIDER Telomerase and Cancer Stem Cells Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 205 - 208. [Abstract] [PDF]

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