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Blood, 15 January 2007, Vol. 109, No. 2, pp. 524-532. Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2006-07-035089. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-07-035089v1 109/2/524    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 Xin, Z.-T. Articles by Ly, H. Search for Related Content PubMed PubMed Citation Articles by Xin, Z.-T. Articles by Ly, H. Related Collections Hematopoiesis and Stem Cells Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Functional characterization of natural telomerase mutations found in patients with hematologic disorders Zhong-Tao Xin1, Adam D. Beauchamp1, Rodrigo T. Calado2, Jennifer W. Bradford1, Joshua A. Regal2, Aarthi Shenoy2, Yuying Liang1, Peter M. Lansdorp3, Neal S. Young2, and Hinh Ly1, 1 Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; 2 National Heart, Lung, and Blood Institute, Hematology Branch, Bethesda, MD; 3 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada Human telomerase hTERC RNA serves as a template for the catalytic hTERT protein to synthesize telomere repeats at chromosome ends. We have recently shown that some patients with bone marrow failure syndromes are heterozygous carriers for hTERC or hTERT mutations. These sequence variations usually lead to a compromised telomerase function by haploinsufficiency. Here, we provide functional characterization of an additional 8 distinct hTERT sequence variants and 5 hTERC variants that have recently been identified in patients with dyskeratosis congenita (DC) or aplastic anemia (AA). Among the mutations, 2 are novel telomerase variants that were identified in our cohort of patients. Whereas most of the sequence variants modulate telomerase function by haploinsufficiency, 2 hTERC variants with sequence changes located within the template region appear to act in a dominant-negative fashion. Inherited telomerase gene mutations, therefore, operate by various mechanisms to shorten telomere lengths, leading to limited marrow stem cell reserve and renewal capacity in patients with hematologic disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Meznikova, N. Erdmann, R. Allsopp, and L. A. Harrington Telomerase reverse transcriptase-dependent telomere equilibration mitigates tissue dysfunction in mTert heterozygotes Dis. Model. Mech., November 1, 2009; 2(11-12): 620 - 626. [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] T. M. Errington, D. Fu, J. M. Y. Wong, and K. Collins Disease-Associated Human Telomerase RNA Variants Show Loss of Function for Telomere Synthesis without Dominant-Negative Interference Mol. Cell. Biol., October 15, 2008; 28(20): 6510 - 6520. [Abstract] [Full Text] [PDF] T. Vulliamy, R. Beswick, M. Kirwan, A. Marrone, M. Digweed, A. Walne, and I. Dokal From the Cover: Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita PNAS, June 10, 2008; 105(23): 8073 - 8078. [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] G. Aubert and P. M. Lansdorp Telomeres and Aging Physiol Rev, April 1, 2008; 88(2): 557 - 579. [Abstract] [Full Text] [PDF] P. M. Lansdorp Telomeres, stem cells, and hematology Blood, February 15, 2008; 111(4): 1759 - 1766. [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] R. T. Calado, S. A. Graf, K. L. Wilkerson, S. Kajigaya, P. J. Ancliff, Y. Dror, S. J. Chanock, P. M. Lansdorp, and N. S. Young Mutations in the SBDS gene in acquired aplastic anemia Blood, August 15, 2007; 110(4): 1141 - 1146. [Abstract] [Full Text] [PDF] A. J. Walne, T. Vulliamy, A. Marrone, R. Beswick, M. Kirwan, Y. Masunari, F.-h. Al-Qurashi, M. Aljurf, and I. Dokal Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10 Hum. Mol. Genet., July 1, 2007; 16(13): 1619 - 1629. [Abstract] [Full Text] [PDF]

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