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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4198-4205. Prepublished online as a Blood First Edition Paper on September 4, 2007; DOI 10.1182/blood-2006-12-062851. This Article Full Text (PDF) All Versions of this Article: blood-2006-12-062851v1 110/13/4198    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 Marrone, A. Articles by Dokal, I. Search for Related Content PubMed PubMed Citation Articles by Marrone, A. Articles by Dokal, I. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 13, 2006 Accepted August 25, 2007 Telomerase reverse transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome Anna Marrone*, Amanda Walne, Hannah Tamary, Yuka Masunari, Michael Kirwan, Richard Beswick, Tom Vulliamy, and Inderjeet Dokal Academic Unit of Paediatrics, Inst of Cell & Molecular Science, Barts & The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom Department of Paediatric Haematology, Schneider Children's Medical Center of Israel, Sackler School of Medicine, Tel Aviv University, Petah-Tikva, Israel * Corresponding author; email: a.f.marrone{at}qmul.ac.uk. Dyskeratosis congenita (DC) is a multi-system bone marrow failure syndrome characterized by a triad of muco-cutaneous abnormalities and an increased predisposition to malignancy. X-linked DC is due to mutations in DKC1, while heterozygous mutations in TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase) have been found in autosomal dominant DC. Many patients with DC remain uncharacterized, particularly families displaying autosomal recessive (AR) inheritance. We have now identified novel homozygous TERT mutations in two unrelated consanguineous families, where the index case presented with classical DC or the more severe variant, Hoyeraal-Hreidarsson (HH) syndrome. These TERT mutations resulted in reduced telomerase activity and extremely short telomeres. As these mutations are homozygous, these patients are predicted to have significantly reduced telomerase activity in vivo. Interestingly, in contrast to patients with heterozygous TERT mutations or hemizygous DKC1 mutations, these two homozygous TERT patients were observed to have higher-than-expected TERC levels when compared to controls. Collectively, the findings from this study demonstrate that homozygous TERT mutations, resulting in a pure but severe telomerase deficiency, produce a phenotype of classical AR-DC and its severe variant, the HH syndrome. 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] H. Fujii, L. Shao, I. Colmegna, J. J. Goronzy, and C. M. Weyand Telomerase insufficiency in rheumatoid arthritis PNAS, March 17, 2009; 106(11): 4360 - 4365. [Abstract] [Full Text] [PDF] A. J. Walne, T. Vulliamy, R. Beswick, M. Kirwan, and I. 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M. Lansdorp Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita Blood, May 1, 2008; 111(9): 4523 - 4531. [Abstract] [Full Text] [PDF] U. Tabori and D. Malkin Risk Stratification in Cancer Predisposition Syndromes: Lessons Learned from Novel Molecular Developments in Li-Fraumeni Syndrome Cancer Res., April 1, 2008; 68(7): 2053 - 2057. [Abstract] [Full Text] [PDF] H.-Y. Du, E. Pumbo, P. Manley, J. J. Field, S. J. Bayliss, D. B. Wilson, P. J. Mason, and M. Bessler Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene Blood, February 1, 2008; 111(3): 1128 - 1130. [Abstract] [Full Text] [PDF]

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