Functional analysis of heterozygous plasma dysfibrinogens derived from three families of gamma Asn308Lys, and haplotype analysis of these families

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  • SOYA Keisuke
    Department of Laboratory Medicine, Shinshu University Hospital Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University
  • ARAI Shinpei
    Department of Laboratory Medicine, Shinshu University Hospital
  • TAKEZAWA Yuka
    Department of Laboratory Medicine, Shinshu University Hospital
  • SUGANO Mitsutoshi
    Department of Laboratory Medicine, Shinshu University Hospital
  • TERASAWA Fumiko
    Department of Biomedical Laboratory Sciences, School of Health Sciences, Shinshu University
  • OKUMURA Nobuo
    Department of Biomedical Laboratory Sciences, School of Health Sciences, Shinshu University

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Other Title
  • 異常フィブリノゲンヘテロ接合体γ鎖Asn308Lys3家系のフィブリノゲン機能比較とハプロタイプ解析

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We found and identified five heterozygous dysfibrinogenemias with γN308K (AAT→AAG) mutation in three families by coagulation screening tests and direct sequence analysis of PCR-amplified DNA fragments. Three dysfibrinogens were designated as fibrinogens Matsumoto II, Matsumoto XI, and Nagano I. The patients fibrinogens purified from plasma using immunoaffinity-chromatography were subjected to thrombin-catalyzed fibrin polymerization. In the absence of Ca2+, the patients’ fibrinogens showed impaired thrombin-catalyzed fibrin polymerization in comparison with normal control fibrinogen. On the other hand, in the presence of 1.0 mM Ca2+, the polymerization of all the patients fibrinogen was improved as compared with those in the absence of Ca2+. Although Single Nucleotide Polymorphism (SNPs) analysis showed that all patients might be derived from a single proband of mutation, the degree of impairment of polymerization was markedly different among affected patient’s fibrinogens. Moreover, SDS-PAGE analysis indicated that the ratio of the amount of the mutant γ-chain to that of the normal γ-chain was not significantly different among the affected patients fibrinogens. In conclusion, we speculate that the increase in the amount of heterodimers consisting of normal and mutant γ-chains (namely, the decrease in the amount of homodimers consisting of the normal γ-chain) leads to the marked impairment of thrombin-catalyzed fibrin polymerization.

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