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Blood, 15 April 2006, Vol. 107, No. 8, pp. 3084-3090. Prepublished online as a Blood First Edition Paper on January 5, 2006; DOI 10.1182/blood-2005-07-2638. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-07-2638v1 107/8/3084    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 Mankad, A. Articles by Grompe, M. Search for Related Content PubMed PubMed Citation Articles by Mankad, A. Articles by Grompe, M. Related Collections Hematopoiesis and Stem Cells Red Cells Stem Cells in Hematology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Natural gene therapy in monozygotic twins with Fanconi anemia Anuj Mankad, Toshiyasu Taniguchi, Barbara Cox, Yassmine Akkari, R. Keaney Rathbun, Lora Lucas, Grover Bagby, Susan Olson, Alan D'Andrea, and Markus Grompe From the Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR; the Dana Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, MA; and the Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. Monozygotic twin sisters, with nonhematologic symptoms of Fanconi anemia (FA), were discovered to be somatic mosaics for mutations in the FANCA gene. Skin fibroblasts, but not lymphocytes or committed hematopoietic progenitors, were sensitive to DNA cross-linking agents. Molecular analysis revealed, in skin cells of both twins, a frameshift causing deletion in exon 27 (2555T) and an exon 28 missense mutation (2670G>A/R880Q). The latter resulted in primarily cytoplasmic expression and reduced function of the mutant FANCA (R880Q) protein. Surprisingly, the same acquired exon 30 missense change (2927G>A/E966K) was detected in the hematopoietic cells of both sisters, but not in their fibroblasts, nor in either parent. This compensatory mutation existed in cis with the maternal exon 28 mutation, and it restored function and nuclear localization of the resulting protein. Both sisters have been free of hematologic symptoms for more than 2 decades, suggesting that this de novo mutation occurred prenatally in a single hematopoietic stem cell (HSC) in one twin and that descendants of this functionally corrected HSC, via intra-uterine circulation, repopulated the blood lineages of both sisters. This finding suggests that treating FA patients with gene therapy might require transduction of only a few hematopoietic stem cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. P. Alter, G. M. Baerlocher, S. A. Savage, S. J. Chanock, B. B. Weksler, J. P. Willner, J. A. Peters, N. Giri, and P. M. Lansdorp Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita Blood, September 1, 2007; 110(5): 1439 - 1447. [Abstract] [Full Text] [PDF]

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