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

R. Asselta, M. Robusto, P. Braidotti, F. Peyvandi, S. Nastasio, L. D'Antiga, V. N. Perisic, G. Maggiore, S. Caccia, S. Duga

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1459-1467
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume13
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

Keywords

  • Congenital
  • Fibrinogen
  • Hypofibrinogenemia
  • Immunocytochemistry
  • Liver diseases
  • Missense mutation

ASJC Scopus subject areas

  • Hematology

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