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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3594-3600. Prepublished online as a Blood First Edition Paper on July 30, 2008; DOI 10.1182/blood-2008-05-153445. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-05-153445v1 112/9/3594    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 Walne, A. J. Articles by Dokal, I. Search for Related Content PubMed PubMed Citation Articles by Walne, A. J. Articles by Dokal, I. Related Collections Hematopoiesis and Stem Cells Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes Amanda J. Walne1,*, Tom Vulliamy1,*, Richard Beswick1, Michael Kirwan1, and Inderjeet Dokal1 1 Centre for Paediatrics, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, London, United Kingdom Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and a predisposition to cancer. The genetic basis of DC remains unknown in more than 60% of patients. Mutations have been identified in components of the telomerase complex (dyskerin, TERC, TERT, NOP10, and NHP2), and recently in one component of the shelterin complex TIN2 (gene TINF2). To establish the role of TINF2 mutations, we screened DNA from 175 uncharacterised patients with DC as well as 244 patients with other bone marrow failure disorders. Heterozygous coding mutations were found in 33 of 175 previously uncharacterized DC index patients and 3 of 244 other patients. A total of 21 of the mutations affected amino acid 282, changing arginine to histidine (n = 14) or cysteine (n = 7). A total of 32 of 33 patients with DC with TINF2 mutations have severe disease, with most developing aplastic anaemia by the age of 10 years. Telomere lengths in patients with TINF2 mutations were the shortest compared with other DC subtypes, but TERC levels were normal. In this large series, TINF2 mutations account for approximately 11% of all DC, but they do not play a significant role in patients with related disorders. This study emphasises the role of defective telomere maintenance on human disease. 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] B. P. Alter, N. Giri, S. A. Savage, and P. S. Rosenberg Cancer in dyskeratosis congenita Blood, June 25, 2009; 113(26): 6549 - 6557. [Abstract] [Full Text] [PDF] H. He, Y. Wang, X. Guo, S. Ramchandani, J. Ma, M.-F. Shen, D. A. Garcia, Y. Deng, A. S. Multani, M. J. You, et al. Pot1b Deletion and Telomerase Haploinsufficiency in Mice Initiate an ATR-Dependent DNA Damage Response and Elicit Phenotypes Resembling Dyskeratosis Congenita Mol. Cell. Biol., January 1, 2009; 29(1): 229 - 240. [Abstract] [Full Text] [PDF]

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