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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-02-0387. This Article Full Text (PDF) All Versions of this Article: 2002-02-0387v1 100/6/2040    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 Yu, C. Articles by Raskind, W. H Search for Related Content PubMed PubMed Citation Articles by Yu, C. Articles by Raskind, W. H Social Bookmarking                   What's this? Submitted February 11, 2002 Accepted April 16, 2002 X-linked thrombocytopenia with thalassemia due to a mutation in the amino-finger of GATA-1 affecting DNA-binding rather than FOG-1 interaction Channing Yu, Kathy K Niakan, Mark Matsushita, George Stamatoyannopooulos, Stuart H Orkin*, and Wendy H Raskind Division of Hematology/Oncology, Children's Hospital, HHMI, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, none; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, none Division of Medical genetics, University of Washington, Seattle, WA, USA Division of Hematology/Oncology, Children's Hospital, HHMI, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA * Corresponding author; email: orkin{at}rascal.med.harvard.edu. Transcription factor GATA-1 is essential for development of erythroid cells and megakaryocytes. Each of its two zinc-fingers is critical for normal function. The C-terminal finger is necessary for DNA binding. The N-finger mediates interaction with FOG-1, a cofactor for GATA-1, and also modulates DNA-binding affinity, notably at complex or "palindromic" GATA sites. Residues of the N-finger mediating interaction with FOG-1 lie on the surface of the N-finger facing away from DNA. Strong sequence conservation of residues facing DNA suggests that this other surface may also have an important role. We report here that a syndrome of X-linked thrombocytopenia with thalassemia in humans is tightly linked to a missense mutation (R216 to Q) in the GATA-1 N-finger. To investigate the functional consequences of this substitution, we used site-directed mutagenesis to alter the corresponding residue in GATA-1. Compared to wild type GATA-1, R216Q GATA-1 shows comparable affinity to single GATA-sites but decreased affinity to palindromic sites. R216Q GATA-1 interacts with FOG-1 comparably to wild type GATA-1. R216Q GATA-1 supports erythroid maturation of GATA-1- erythroid cells, albeit at a reduced efficiency compared to wild type GATA-1. Together, these findings suggest that residues of the N-finger of GATA-1 facing DNA contribute to GATA-1 function apart from interaction with the cofactor FOG-1. This is also the first example of ß-thalassemia in man due to a mutation in an erythroid transcription factor. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. E. Elagib, I. S. Mihaylov, L. L. Delehanty, G. C. Bullock, K. D. Ouma, J. F. Caronia, S. L. Gonias, and A. N. Goldfarb Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation Blood, December 15, 2008; 112(13): 4884 - 4894. [Abstract] [Full Text] [PDF] C. L. Balduini, E. De Candia, and A. 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