Genotypic and phenotypic features of Japanese patients with mild to moderate hemophilia A
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ORIGINAL ARTICLE
Genotypic and phenotypic features of Japanese patients with mild to moderate hemophilia A Hiroshi Inaba • Keiko Shinozawa • Ikuo Seita • Manabu Otaki • Takashi Suzuki • Takeshi Hagiwara Kagehiro Amano • Katsuyuki Fukutake
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Received: 7 February 2013 / Revised: 12 April 2013 / Accepted: 15 April 2013 Ó The Japanese Society of Hematology 2013
Abstract Hemophilia A is the most common inherited bleeding disorder. To better understand the genotypic and phenotypic features of Japanese patients with mild to moderate hemophilia A, we studied 29 unrelated patients with more than 1 % FVIII activity (FVIII:C). Differences were observed in nine of 21 patients in measured FVIII:C levels between the one-stage clotting and chromogenic assays. We identified a mutation in F8 in 28 of the 29 patients. Mutations in two amino acids, Y492 and R550, were detected at a much higher frequency in our patients than in the international hemophilia A mutation database. We demonstrated that all five patients with the Y492C mutation have an identical F8 haplotype that is unique to them, suggesting that the mutation may have originated from a common ancestor. Because nonsevere, moderate to mild, hemophilia patients have a longer lifespan, mutations that cause non-severe phenotypes tend to persist in the population. We believe that the Y492C mutation is a distinctive feature of Japanese patients with mild hemophilia A. The identification of a high frequency of R550 mutation that underlies the discrepancies in FVIII:C measurements in the present study suggests that Japanese patients with mild hemophilia may require careful characterization. Keywords Hemophilia A Founder effect Mutation Discrepancy
H. Inaba (&) I. Seita M. Otaki T. Suzuki T. Hagiwara K. Amano K. Fukutake Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan e-mail: [email protected] K. Shinozawa K. Amano K. Fukutake Department of Molecular Genetics of Coagulation Disorders, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Introduction Hemophilia A (MIM ?306700) is the most common inherited bleeding disorder caused by a quantitative or qualitative abnormality of the blood coagulation factor VIII (FVIII). The clinical severity of hemophilia A correlates well with the residual factor VIII activity (FVIII:C) in circulating blood, and the presence of small amounts of FVIII:C markedly reduces the clinical severity. Mild to moderate hemophilia A, generally presenting with mild or negligible bleeding symptoms, is defined as FVIII:C of more than 1 % [1]. About 60 % of hemophilia A patients are classified into this category [2]. The factor VIII gene (F8) is located on the most distal band of chromosome X (Xq28) and spans over 186 kb. This large gene consists of 26 exons and 25 introns, and encodes 2,351 amino acids. Since the cloning of F8 in 1984 [3–6], numerous analyses regarding F8 have been performed to identify the mutation(s) responsible for h
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