Heterozygous Bβ-chain C-terminal 12 amino acid elongation variant, BβX462W (Kyoto VI), showed dysfibrinogenemia

Blood Coagul Fibrinolysis. 2012 Jan;23(1):87-90. doi: 10.1097/MBC.0b013e32834cb243.

Abstract

A heterozygous patient with dysfibrinogenemia with slight bleeding and no thrombotic complications was diagnosed with fibrinogen Kyoto VI (K-VI). To elucidate the genetic mutation(s) and characterize the variant protein, we performed the following experiments and compared with identical and similar variants that have already been reported. The proposita's PCR-amplified DNA was analyzed by sequencing and her purified plasma fibrinogen underwent SDS-PAGE followed by immunoblotting, fibrin polymerization, and scanning electron microscopic observation of fibrin clot and fibers. Sequence analyses showed that K-VI fibrinogen substituted W (TGG) for terminal codon (TAG), resulting in 12 amino acid elongation 462-473 (WSPIRRFLLFCM) in the Bβ-chain. Protein analyses indicated that the presence of some albumin-binding variant fibrinogens and a dimeric molecule of variant fibrinogens reduced fibrin polymerization, with a thinner fiber and aberrant fibrin network. These results are almost the same as for the identical variant of Magdeburg, however, different from the similar variant of Osaka VI [12 amino acid elongation 462-473 (KSPIRRFLLFCM) in the Bβ-chain] in the presence of variant forms and clot structure. We speculate the side-chain difference at 462 residues, W in K-VI, K in Osaka VI, and/or the difference in the presence of disulfide bridged forms of variant fibrinogens, led to the notable difference in the fibrin bundle network. Although a strong evolutional and structural association between Bβ-chain and γ-chain molecules is established, the corresponding recombinant 15 residue elongation variants of the fibrinogen γ-chain showed reduced assembly and secretion.

MeSH terms

  • Afibrinogenemia / blood
  • Afibrinogenemia / genetics*
  • Amino Acids
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Fibrinogen / genetics*
  • Fibrinogen / metabolism
  • Humans
  • Microscopy, Electron, Scanning
  • Middle Aged

Substances

  • Amino Acids
  • Fibrinogen