Hepatic fibrinogen storage disease: identification of two novel mutations (p.Asp316Asn, fibrinogen Pisa and p.Gly366Ser, fibrinogen Beograd) impacting on the fibrinogen γ-module

J Thromb Haemost. 2015 Aug;13(8):1459-67. doi: 10.1111/jth.13021. Epub 2015 Jul 14.


Background: Quantitative fibrinogen deficiencies (hypofibrinogenemia and afibrinogenemia) are rare congenital disorders characterized by low/unmeasurable plasma fibrinogen antigen levels. Their genetic basis is invariably represented by mutations within the fibrinogen genes (FGA, FGB and FGG coding for the Aα, Bβ and γ chains). Currently, only four mutations (p.Gly284Arg, p.Arg375Trp, delGVYYQ 346-350, p.Thr314Pro), all affecting the fibrinogen γ chain, have been reported to cause fibrinogen storage disease (FSD), a disorder characterized by protein aggregation, endoplasmic reticulum retention and hypofibrinogenemia.

Objectives: To investigate the genetic basis of FSD in two hypofibrinogenemic patients.

Methods: The mutational screening of the fibrinogen genes was performed by direct DNA sequencing. The impact of identified mutations on fibrinogen structure was investigated by in-silico molecular modeling. Liver histology was evaluated by light microscopy, electron microscopy and immunocytochemistry.

Results: Here, we describe two hypofibrinogenemic children with persistent abnormal liver function parameters. Direct sequencing of the coding portion of fibrinogen genes disclosed two novel FGG missense variants (p.Asp316Asn, fibrinogen Pisa; p.Gly366Ser, fibrinogen Beograd), both present in the heterozygous state and affecting residues located in the fibrinogen C-terminal γ-module. Liver sections derived from biopsies of the two patients were examined by immunocytochemical analyses, revealing hepatocyte cytoplasmic inclusions immunoreactive to anti-fibrinogen antibodies.

Conclusions: Our work strongly confirms the clustering of mutations causing FSD in the fibrinogen γ chain between residues 284 and 375. Based on an in-depth structural analysis of all FSD-causing mutations and on their resemblance to mutations leading to serpinopathies, we also comment on a possible mechanism explaining fibrinogen polymerization within hepatocytes.

Keywords: congenital; fibrinogen; hypofibrinogenemia; immunocytochemistry; liver diseases; missense mutation.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Afibrinogenemia / diagnosis
  • Afibrinogenemia / genetics*
  • Afibrinogenemia / metabolism
  • Amino Acid Sequence
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Fibrinogen / chemistry
  • Fibrinogen / genetics*
  • Fibrinogen / metabolism
  • Fibrinogens, Abnormal / chemistry
  • Fibrinogens, Abnormal / genetics*
  • Fibrinogens, Abnormal / metabolism
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Liver / metabolism*
  • Liver Diseases / diagnosis
  • Liver Diseases / genetics*
  • Liver Diseases / metabolism
  • Liver Function Tests
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Phenotype
  • Protein Conformation
  • Structure-Activity Relationship


  • Fibrinogens, Abnormal
  • fibrinogen Beograd
  • fibrinogen Pisa
  • fibrinopeptides gamma
  • Fibrinogen

Associated data

  • GENBANK/AF229198
  • GENBANK/M64982