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Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 92 No. 8 (October 15), 1998: pp. 2750-2758 A Gln747Pro Substitution in the IIb Subunit Is Responsible for a Moderate IIb3 Deficiency in Glanzmann Thrombasthenia Seiji Tadokoro, Yoshiaki Tomiyama, Shigenori Honda, Morio Arai, Naomasa Yamamoto, Masamichi Shiraga, Satoru Kosugi, Yuzuru Kanakura, Yoshiyuki Kurata, and Yuji Matsuzawa From The Second Department of Internal Medicine, Osaka University Medical School, Osaka, Japan; the Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan; the Department of Clinical Pathology, Tokyo Medical College, Tokyo, Japan; and the Department of Cardiovascular Research, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. To clarify a molecular defect responsible for moderate IIb3 deficiency, we examined two unrelated patients, MT and MS, suffering from type II and type I Glanzmann thrombasthenia (GT), respectively. Sequence analysis of polymerase chain reaction (PCR) fragments derived from platelet mRNA showed a single AC substitution at nucleotide (nt) 2334 leading to a Gln747 Pro in IIb in both patients. Allele-specific restriction enzyme analysis (ASRA) of genomic DNA demonstrated that patient MT was homozygous for the Gln747Pro substitution and patient MS was compound heterozygous for this substitution and for an RNA splice mutation at the consensus sequence of the splice acceptor site of exon 18 (AGAA). Furthermore, ASRA showed that, among 17 unrelated Japanese GT patients, this Gln747Pro substitution was detected in 4 patients, including MT and MS (homozygous, 2 patients; heterozygous, 2 patients). Cotransfection of Pro747IIb and 3 constructs into 293 cells resulted in moderate reduction in the amount of IIb3 within the transfected cells as well as on the cell surface. However, Pro747IIb3 bound the ligand mimetic monoclonal antibody (MoAb) PAC-1 after activation of IIb3 by the MoAb PT25-2, suggesting that the mutant IIb3 possesses the ligand-binding function. The association between the mutant proIIb and 3 was not disturbed. Surface labeling and pulse chase study showed that the Gln747Pro substitution moderately impaired both intracellular transport of the IIb3 heterodimers to the Golgi apparatus and endoproteolytic cleavage of proIIb into heavy and light chains. By contrast, replacement of Gln747 with Ala by mutagenesis did not impair IIb3 expression on the cell surface. These results suggest that the presence of Pro, rather than the absence of Gln, at amino acid residue 747 on IIb is responsible for moderate IIb3 deficiency. © 1998 by The American Society of Hematology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Losonczy, N. Rosenberg, Z. Boda, G. Vereb, J. Kappelmayer, H. Hauschner, Z. Bereczky, and L. Muszbek Three novel mutations in the glycoprotein IIb gene in a patient with type II Glanzmann thrombasthenia Haematologica, May 1, 2007; 92(5): 698 - 701. [Abstract] [Full Text] [PDF] N. Rosenberg, R. Yatuv, V. Sobolev, H. Peretz, A. Zivelin, and U. Seligsohn Major mutations in calf-1 and calf-2 domains of glycoprotein IIb in patients with Glanzmann thrombasthenia enable GPIIb/IIIa complex formation, but impair its transport from the endoplasmic reticulum to the Golgi apparatus Blood, June 15, 2003; 101(12): 4808 - 4815. [Abstract] [Full Text] [PDF] T. Kiyoi, Y. Tomiyama, S. Honda, S. Tadokoro, M. Arai, H. Kashiwagi, S. Kosugi, H. Kato, Y. Kurata, and Y. 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