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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 6, 2008 Accepted July 21, 2008 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 Walne*, Thomas J Vulliamy, Richard Beswick, Michael Kirwan, and Inderjeet Dokal Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom * Corresponding author; email: a.walne{at}qmul.ac.uk. Dyskeratosis congenita (DC) is a multi-system bone marrow failure syndrome characterised by a triad of mucocutaneous abnormalities and a predisposition to cancer. The genetic basis of DC remains unknown in >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 cases of DC as well as 244 patients with other bone marrow failure disorders. Heterozygous coding mutations were found in 33/175 previously uncharacterised DC index cases and 3/244 other patients. 21 of the mutations affected amino acid 282 changing arginine to histidine (n=14) or cysteine (n=7). 32/33 DC patients with TINF2 mutations have severe disease with the majority developing aplastic anaemia by the age of 10 years. Telomere lengths in patients with TINF2 mutations were the shortest compared to other DC subtypes but TERC levels were normal. In this large series, TINF2 mutations account for ~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 has 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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