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

AbstractBACKGROUND:
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.
AuthorsR Asselta, M Robusto, P Braidotti, F Peyvandi, S Nastasio, L D'Antiga, V N Perisic, G Maggiore, S Caccia, S Duga
JournalJournal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 13 Issue 8 Pg. 1459-67 (Aug 2015) ISSN: 1538-7836 [Electronic] England
PMID26039544 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)
Copyright© 2015 International Society on Thrombosis and Haemostasis.
Chemical References
  • Fibrinogens, Abnormal
  • fibrinogen Beograd
  • fibrinogen Pisa
  • fibrinopeptides gamma
  • Fibrinogen
Topics
  • Afibrinogenemia (diagnosis, genetics, metabolism)
  • Amino Acid Sequence
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Fibrinogen (chemistry, genetics, metabolism)
  • Fibrinogens, Abnormal (chemistry, genetics, metabolism)
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Liver (metabolism)
  • Liver Diseases (diagnosis, genetics, metabolism)
  • Liver Function Tests
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense
  • Phenotype
  • Protein Conformation
  • Structure-Activity Relationship

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