PDF herunterladen
Thromb Haemost 2000; 84(01): 49-53
DOI: 10.1055/s-0037-1613966
Commentary
Schattauer GmbH

A Case of Congenital Afibrinogenemia: Fibrinogen Hakata, a Novel Nonsense Mutation of the Fibrinogen γ-Chain Gene

Hiroko Iida
1   From the Department of Clinical Chemistry and Laboratory Medicine, Fukuoka, Japan
,
Eiichi Ishii
3   Department of Pediatrics, Hamanomachi Hospital, Fukuoka, Japan
,
Mutsuko Nakahara
1   From the Department of Clinical Chemistry and Laboratory Medicine, Fukuoka, Japan
,
Michiyo Urata
1   From the Department of Clinical Chemistry and Laboratory Medicine, Fukuoka, Japan
,
Machiko Wakiyama
1   From the Department of Clinical Chemistry and Laboratory Medicine, Fukuoka, Japan
,
Masako Kurihara
1   From the Department of Clinical Chemistry and Laboratory Medicine, Fukuoka, Japan
,
Kumiko Watanabe
1   From the Department of Clinical Chemistry and Laboratory Medicine, Fukuoka, Japan
,
Takeshi Kai
3   Department of Pediatrics, Hamanomachi Hospital, Fukuoka, Japan
,
Kenji Ihara
2   Department of Pediatrics, Kyushu University Hospital, Fukuoka, Japan
,
Sachiko Kinoshita
1   From the Department of Clinical Chemistry and Laboratory Medicine, Fukuoka, Japan
,
Naotaka Hamasaki
1   From the Department of Clinical Chemistry and Laboratory Medicine, Fukuoka, Japan
› InstitutsangabenWe wish to thank Professor Sheshadri Narayaman, New York Medical College (USA), for critically reading this manuscript. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (to NH), and by a P&P Grant from Kyushu University (to NH).
Weitere Informationen

Publikationsverlauf

Received 30. November 1999

Accepted after resubmission 15. Februar 2000

Publikationsdatum:
10. Dezember 2017 (online)

    Lizenzen und Reprints

Summary

Congenital afibrinogenemia due to a novel homozygous nonsense mutation of the fibrinogen γ-chain gene, fibrinogen Hakata, was found in an 18-year-old Japanese girl who had received supplemental fibrinogen therapy since she was 4 months old. The plasma fibrinogen concentrations of the proband were measured as less than 10 mg/dl by a functional method and less than 17 mg/dl by an immunological method. Fibrinogen concentrations of her family were in the range of 94-164 mg/dl. The proband and her family had no other clinical symptoms.

Genomic DNA of the proband and her family was isolated from leukocytes, and all exons of fibrinogen subunits and their intron/exon boundaries were analyzed. A genetic mutation, a guanine-to-thymine (G-to-T) transversion at the nucleotide position of 5860, was identified on exon 7 of the γ-chain gene. This mutation changed the codon for the 231st residue of the γ chain from GAG (Glu) to TAG (stop). No other mutation was observed. Aα, Bβ and γ chains were observed in plasma of the heterozygous family members. However, only a trace amount of Aα chain and no γ chain was detected in the plasma of the proband.

Keywords

Afibrinogenemia - γ chain of fibrinogen - nonsense mutation - gene analysis
 

  • References

  • 1 Martinez J. Congenital dysfibrinogenemia. Curr Opin Hematol 1997; 04: 357-65.
    CrossrefPubMedGoogle Scholar
  • 2 Galanakis DK. Dysfibrinogenemia. Clin Lab Med 1984; 04: 395-418.
    CrossrefPubMedGoogle Scholar
  • 3 Beck EA. Congenital abnormalities of fibrinogen. Clin Haematol 1979; 08: 169-81.
    PubMedGoogle Scholar
  • 4 Goodwin TM. Congenital hypofibrinogenemia in pregnancy. Obstet Gynecol Surv 1989; 44: 157-61.
    CrossrefPubMedGoogle Scholar
  • 5 De Marco L, Girolami A, Zimmerman TS, Ruggeri ZM. von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia. J Clin Invest 1986; 77: 1272-7.
    CrossrefPubMedGoogle Scholar
  • 6 Henschen AH. Human fibrinogen-structural variants and functional sites. Thromb Haemost 1993; 70: 42-7.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 7 Matsuda M. The structure-function relationship of hereditary dysfibrinogens. Int J Hematol 1996; 64: 167-79.
    CrossrefPubMedGoogle Scholar
  • 8 Neerman-Arbez M, Honsberger A, Antonarakis SE, Morris MA. Deletion of the fibrinogen alpha-chain gene (FGA) causes congenital afibrogenemia. J Clin Invest 1999; 103: 215-8.
    CrossrefPubMedGoogle Scholar
  • 9 Zhang JZ, Redman CM. Role of interchain disulfide bonds on the assembly and secretion of human fibrinogen. J Biol Chem 1994; 269: 652-8.
    PubMedGoogle Scholar
  • 10 Kamura T, Tsuda H, Yae Y, Hattori S, Ohga S, Shibata Y, Kawabata S, Hamasaki N. An abnormal fibrinogen Fukuoka II (Gly-Bβ15-Cys) characterized by defective fibrin lateral association and mixed disulfide formation. J Biol Chem 1995; 270: 29392-9.
    CrossrefPubMedGoogle Scholar
  • 11 Ridgway HJ, Brennan SO, Faed JM, George PM. Fibrinogen Otago: a major a chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage. Br J Haematol 1997; 98: 632-9.
    CrossrefPubMedGoogle Scholar
  • 12 Pizzolato MA, Goni FR, Salvarezza RC. Immunofixation on cellulose acetate: an improved screening method for monoclonal immunoglobulins. J Immunol Methods 1979; 26: 365-8.
    CrossrefPubMedGoogle Scholar
  • 13 Yamazaki T, Sugiura I, Matsushita T, Kojima T, Kagami K, Takamatsu J, Saito H. A phenotypically neutral dimorphism of protein S: the substitution of Lys155 by Glu in the second EGF domain predicted by an A to G base exchange in the gene. Thromb Res 1993; 70: 395-403.
    CrossrefPubMedGoogle Scholar
  • 14 Cote HC, Lord ST, Pratt KP. γ-chain dysfibrinogenemias: molecular structure-function relationships of naturally occurring mutations in the γ chain of human fibrinogen. Blood 1998; 92: 2195-212.
    PubMedGoogle Scholar
  • 15 Cierniewski CS, Budzynski AZ. Localization of the cross-linking site of GPRVVERHK in the γ-chain of human fibrinogen. Eur J Biochem 1993; 218: 321-5.
    CrossrefPubMedGoogle Scholar
  • 16 Dang CV, Ebert RF, Bell WR. Localization of a fibrinogen calcium binding site between γ-subunit positions 311 and 336 by terbium fluorescence. J Biol Chem 1985; 260: 9713-9.
    PubMedGoogle Scholar
  • 17 Varadi A, Scheraga HA. Localization of segments essential for polymerization and for calcium binding in the γ-chain of human fibrinogen. Biochemistry 1986; 25: 519-28.
    CrossrefPubMedGoogle Scholar
  • 18 Shimizu A, Nagel GM, Doolittle RF. Photoaffinity labeling of the primary fibrin polymerization site: isolation and characterization of a labeled cyanogen bromide fragment corresponding to γ-chain residue 337-79. Proc Natl Acad Sci USA 1992; 89: 2888-92.
    CrossrefPubMedGoogle Scholar
  • 19 Yamazumi K, Doolittle RF. Photoaffinity labeling of the primary fibrin polymerization site: localization of the label to γ-chain Tyr-363. Proc Natl Acad Sci USA 1992; 89: 2893-6.
    CrossrefPubMedGoogle Scholar
  • 20 Kloczewiak M, Timmons S, Lukas TJ, Hawiger J. Platelet receptor recognition site on human fibrinogen. Synthesis and structure-function relationship of peptides corresponding to the carboxy-terminal segment of the γ chain. Biochemistry 1984; 23: 1767-74.
    CrossrefPubMedGoogle Scholar
  • 21 Altieri DC, Plescia J, Plow EF. The structural motif glycine 190-valine 202 of the fibrinogen γ chain interacts with CD11b/CD18 integrin (αMβ2, Mac-1) and promotes leukocyte adhesion. J Biol Chem 1993; 268: 1847-53.
    PubMedGoogle Scholar
  • 22 Varadi A, Patthy L. Location of plasminogen-binding sites in human fibrin(ogen). Biochemistry 1983; 22: 2440-6.
    CrossrefPubMedGoogle Scholar
  • 23 Nieuwenhuizen W. Sites in fibrin involved in the acceleration of plasminogen activation by t-PA. Possible role of fibrin polymerization. Thromb Res 1994; 75: 343-7.
    CrossrefPubMedGoogle Scholar
  • 24 Yonekawa O, Voskuilen M, Nieuwenhuizen W. Localization in the fibrinogen γ-chain of a new site that is involved in the acceleration of the tissuetype plasminogen activator-catalyzed activation of plasminogen. Biochem J 1992; 283: 187-91.
    CrossrefPubMedGoogle Scholar
  • 25 Medved L, Litvinovich S, Ugarova T, Matsuka Y, Ingham K. Domain structure and functional activity of the recombinant human fibrinogen γ-module (γ148-411). Biochemistry 1997; 36: 4685-93.
    CrossrefPubMedGoogle Scholar
  • 26 Steinmann C, Jungo M, Beck EA, Lammle B, Furlan M. Fibrinogen Claroanother dysfunctional fibrinogen variant with γ275 arginine-histidine substitution. Thromb Res 1996; 81: 145-50.
    CrossrefPubMedGoogle Scholar
  • 27 Niwa K, Takebe M, Sugo T, Kawata Y, Mimuro J, Asakura S, Sakata Y, Mizushima J, Maeda A, Endo H, Matsuda M. A γ Gly-268 to Glu substitution is responsible for impaired fibrin assembly in a homozygous dysfibrinogen Kurashiki I. Blood 1996; 87: 4686-94.
    PubMedGoogle Scholar
  • 28 Fellowes AP, Brennan SO, Ridgway HJ, Heaton DC, George PM. Electrospray ionization mass spectrometry identification of fibrinogen Banks Peninsula (γ280Tyr-Cys): a new variant with defective polymerization. Br J Haematol 1998; 101: 24-31.
    CrossrefPubMedGoogle Scholar
  • 29 Okumura N, Furihata K, Terasawa F, Ishikawa S, Ueno I, Katsuyama T. Fibrinogen Matsumoto II: γ308 Asn-Lys (AAT-AAG) mutation associated with bleeding tendency. Br J Haematol 1996; 94: 526-8.
    CrossrefPubMedGoogle Scholar
  • 30 Callea F, Brisigotti M, Fabbretti G, Bonino F, Desmet VJ. Hepatic endoplasmic reticulum storage diseases. Liver 1992; 12: 357-62.
    PubMedGoogle Scholar
  • 31 Uzan G, Courtois G, Besmond C, Frain M, Sala-Trepat J, Kahn A, Marguerie G. Analysis of fibrinogen genes in patients with congenital afibrinogenemia. Biochem Biophys Res Commun 1984; 120: 376-83.
    CrossrefPubMedGoogle Scholar
  • 32 Koopman J, Haverkate F, Grimbergen J, Egbring R, Lord ST. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids Aα 461-610 (Lys 461 AAA → stop TAA). Blood 1992; 80: 1972-9.
    PubMedGoogle Scholar
  • 33 Furlan M, Steinmann C, Jungo M, Bogli C, Baudo F, Redaelli R, Fedeli F, Lammle B. A frameshift mutation in Exon V of the A alpha-chain gene leading to truncated A alpha-chains in the homozygous dysfibrinogen Milano III. J Biol Chem 1994; 269: 33129-34.
    PubMedGoogle Scholar
  • 34 Gorkun OV, Lord ST. Recombinant fibrinogen in clot formation. Fibrinolysis 1996; 10 (Suppl. 04) 7.
    PubMedGoogle Scholar
  • 35 Suh TT, Holmback K, Jensen NJ, Daugherty CC, Small K, Simon DJ, Potter S, Degen JL. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 1995; 09: 2020-33.
    CrossrefPubMedGoogle Scholar
  • 36 Huang S, Mulvihill ER, Farrell DH, Chung DW, Davie EW. Biosynthesis of human fibrinogen. Subunit interactions and potential intermediates in assembly. J Biol Chem 1993; 268: 8919-26.
    PubMedGoogle Scholar
  • 37 Roy SN, Procyk R, Kudryk BJ, Redman CM. Assembly and secretion of recombinant human fibrinogen. J Biol Chem 1991; 266: 4758-63.
    PubMedGoogle Scholar