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Thromb Haemost 2002; 88(03): 427-431
DOI: 10.1055/s-0037-1613233
Review Article
Schattauer GmbH

Novel Fibrinogen Truncation with Deletion of Bβ Chain Residues 440-461 causes Hypofibrinogenaemia

Vivienne M. Homer
2   Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand
,
Stephen O. Brennan
2   Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand
,
Paul Ockelford
1   Haematology Department, Auckland Hospital, Auckland, New Zealand
,
Peter M. George
2   Molecular Pathology Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand
› Author Affiliations
Further Information

Publication History

Received 19 February 2002

Accepted after revision 30 April 2002

Publication Date:
08 December 2017 (online)

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Summary

A 24-year-old male with hepatitis C was initially diagnosed with hypofibrinogenaemia during investigations prior to a liver biopsy. He had a low functional and gravimetric fibrinogen concentration of 1.0 mg/mL and DNA sequencing of all exons, exon-intron boundaries and promoter regions of the fibrinogen Aα, Bβ, and γ genes revealed a single heterozygous g→a mutation at nucleotide 8035 of the Bβ gene. This creates a premature stop at the Trp 440 codon and results in a 22-residue truncation of the Bβ chain. Analysis of purified plasma fibrinogen by SDS PAGE, reverse phase HPLC and ESI MS, however, failed to detect any of the truncated chains in the plasma fibrinogen. The non-expression of aberrant molecules was further confirmed by functional analysis, which revealed normal fibrin polymerisation. The principal structural feature of the independently folding βD domain is its five-stranded anti-parallel β sheet. The deletion here of residues 440 to 461 removes the second strand from this sheet structure and appears to impact on the viability of the nascent chain and its ability to be incorporated into mature fibrinogen molecules. The mutation does not however provoke the formation of hepatic inclusion bodies.

Keywords

Hypofibrinogenaemia - chain truncation - strand deletion - D domain - mass spectrometry
 

  • References

  • 1 Doolittle RF. The molecular biology of fibrin. In: The Molecular Basis of Blood Diseases. Stamatoyannopoulos C, Nienhuis AW, Majerus PW, Varmus H. eds Philadelphia: W.B. Saunders Company; 1994: 701-23.
    Search in Google Scholar
  • 2 Henschen AH, McDonagh J. Fibrinogen, fibrin and factor XIII. In: Blood Coagulation. Zwaal RFA, Hemker HC. eds Amsterdam: Elsevier Science Publishers B.V. (Biomedical Division); 1986: 171-241.
    Search in Google Scholar
  • 3 Huang S, Mulvihill ER, Farrell DH, Chung DW, Davie EW. Biosynthesis of human fibrinogen. Subunit interactions and potential intermediates in the assembly. J Biol Chem 1993; 268: 8919-26.
    PubMedSearch in Google Scholar
  • 4 Huang S, Cao Z, Chung DW, Davie EW. The role of βγ and αγ complexes in the assembly of human fibrinogen. J Biol Chem 1996; 271: 27942-7.
    CrossrefPubMedSearch in Google Scholar
  • 5 Bonifacino JS, Weissman AM. Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu Rev Cell Dev Biol 1998; 14: 19-57.
    CrossrefPubMedSearch in Google Scholar
  • 6 Brennan SO, Wyatt JM, Medicina D, Callea F, George PM. Fibrinogen Brescia: Hepatic endoplasmic reticulum storage and hypofibrinogenemia because of a γ284 Gly→Arg mutation. Am J Pathol 2000; 157: 189-96.
    CrossrefPubMedSearch in Google Scholar
  • 7 Callea F, Brisigotti M, Fabbretti G, Bonino F, Desmet VJ. Hepatic endoplasmic reticulum storage diseases. Liver 1992; 12: 357-62.
    PubMedSearch in Google Scholar
  • 8 Ridgway HJ, Brennan SO, Faed JM, George PM. Fibrinogen Otago: a major α chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage. Br J Haematol 1997; 98: 632-9.
    CrossrefPubMedSearch in Google Scholar
  • 9 Wyatt J, Brennan SO, May S, George PM. Hypofibrinogenaemia with compound heterozygosity for two gamma chain mutations – gamma 82 Ala→Gly and an intron two GT→AT splice site mutation. Thromb Haemost 2000; 84: 449-52.
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Brennan SO, Wyatt JM, May S, De Caigney S, George PM. Hypofibrinogenemia due to novel 316 Asp→Tyr substitution in the fibrinogen Bbeta chain. Thromb Haemost 2001; 85: 450-3.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Duga S, Asselta R, Santagostino E, Zeinali S, Simonic T, Malcovati M, Mannucci PM, Tenchini ML. Missense mutations in the human β fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion. Blood 2000; 95: 1336-41.
    PubMedSearch in Google Scholar
  • 12 Brennan SO, Hammonds B, George PM. Aberrant hepatic processing causes removal of activation peptide and primary polymerisation site from fibrinogen Canterbury (Aα20 Val→Asp). J Clin Invest 1995; 96: 2854-8.
    CrossrefPubMedSearch in Google Scholar
  • 13 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-5.
    CrossrefPubMedSearch in Google Scholar
  • 14 Reber P, Furlan M, Rupp C, Kehl M, Henschen AH, Mannucci PM, Beck EA. Characterization of fibrinogen Milano I: amino acid exchange γ330 Asp→Val impairs fibrin polymerization. Blood 1986; 67: 1751-6.
    PubMedSearch in Google Scholar
  • 15 Brennan SO. Electrospray ionisation analysis of human fibrinogen. Thromb Haemost 1997; 78: 1055-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Brennan SO, Hammonds B, Spearing R, George PM. Electrospray ionisation mass spectrometry facilitates detection of fibrinogen (Bβ 14Arg→Cys) mutation in a family with thrombosis. Thromb Haemost 1997; 78: 1484-7.
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Ciulla TA, Sklar RM, Hauser SL. A simple method for DNA purification from peripheral blood. Anal Biochem 1988; 174: 485-8.
    CrossrefPubMedSearch in Google Scholar
  • 18 Saiki RK, Chang CA, Levenson CH, Warren TC, Boehm CD, Kazazian Jr HH, Erlich HA. Diagnosis of sickle cell anemia and beta-thalassemia with enzymatically amplified DNA and nonradioactive allele-specific oligonucleotide probes. N Engl J Med 1988; 319: 537-41.
    CrossrefPubMedSearch in Google Scholar
  • 19 Callea F, de Vos R, Togni R, Tardanico R, Vanstapel MJ, Desmet VJ. Fibrinogen inclusions in liver cells: a new type of ground-glass hepatocyte. Immune light and electron microscopic characterization. Histopathology 1986; 10: 65-73.
    PubMedSearch in Google Scholar
  • 20 Martinez J, MacDonald KA, Palascak JE. The role of sialic acid in the dysfibrinogenemia associated with liver disease: distribution of sialic acid on the constituent chains. Blood 1983; 61: 1196-202.
    PubMedSearch in Google Scholar
  • 21 Yakovlev S, Litvinovich S, Loukinov D, Medved L. Role of the beta-strand insert in the central domain of the fibrinogen gamma-module. Biochemistry 2000; 39: 15721-9.
    CrossrefPubMedSearch in Google Scholar
  • 22 Mosesson MW, Siebenlist KR, Hainfeld JF, Wall JS. The covalent structure of Factor XIIIa crosslinked fibrinogen fibrils. J Struct Biol 1995; 115: 88-101.
    CrossrefPubMedSearch in Google Scholar
  • 23 Mosesson MW, Siebenlist KR, Meh DA, Wall JS, Hainfeld JF. The location of the carboxy-terminal region of γ chains in fibrinogen and fibrin D domains. Proc Natl Acad Sci USA 1998; 95: 10511-6.
    CrossrefPubMedSearch in Google Scholar
  • 24 Duga S, Asselta R, Santagoostino E, Peyvandi F, Malcovati M, Mannucci PM, Tenchini ML. Involvement of Fibrinogen Bβ-Chain Gene in the pathogenesis of congenital afibrinogenaemia. Thromb Haemost. 2001 86. abstract P1108 July supplement.
    PubMedSearch in Google Scholar
  • 25 Guex N, Peitsch MC. SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modelling. Electrophoresis. 1997: 2714-23.
    PubMedSearch in Google Scholar
  • 26 Spraggon G, Everse SJ, Doolittle RF. Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin. Nature 1997; 389: 455-62.
    CrossrefPubMedSearch in Google Scholar