Novel fibrinogen gamma375 Arg-->Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia

Hepatology. 2002 Sep;36(3):652-8. doi: 10.1053/jhep.2002.35063.


The proposita and her sister had chronically elevated liver function test results, and needle biopsy specimens showed scattered eosinophilic inclusions within the hepatocytes. On immunoperoxidase staining, the inclusions reacted strongly with anti-fibrinogen antisera; on electron-microscopic (EM) examination, the material appeared confined to the endoplasmic reticulum (ER) and was densely packed into tubular structures with a swirling fingerprint appearance. Coagulation investigations showed low functional and antigenic fibrinogen concentrations that were indicative of hypofibrinogenemia. Amplification and DNA sequencing showed a heterozygous CGG-->TGG mutation at codon 375 of the fibrinogen gamma chain gene. This novel gamma375 Arg-->Trp substitution segregated with hypofibrinogenemia in 3 family members and was absent from 50 normal controls. When purified plasma fibrinogen chains were examined by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, reverse-phase chromatography, electrospray ionization mass spectrometry, and isoelectric focusing, only normal gamma chains were detected. In conclusion, we propose that this nonconservative mutation causes a conformational change in newly synthesized molecules and that this provokes aggregation within the ER and in turn causes the observed hypofibrinogenemia. Whereas the mutation site, gamma375, is located in the gammaD domain at the jaws of the primary E-to-D polymerization site, purified plasma fibrinogen showed normal polymerization, supporting our contention that molecules with variant chains never reach the circulation but accumulate in the ER.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afibrinogenemia / genetics*
  • Afibrinogenemia / metabolism
  • Child, Preschool
  • Endoplasmic Reticulum / metabolism*
  • Family Health
  • Female
  • Fibrinogen / chemistry
  • Fibrinogen / genetics*
  • Fibrinogen / metabolism
  • Heterozygote
  • Humans
  • Isoelectric Focusing
  • Liver / metabolism*
  • Liver / pathology
  • Point Mutation*
  • Protein Structure, Tertiary


  • Fibrinogen