Fibrinogen Mumbai: Intracellular retention due to a novel G434D mutation in the Bβ-chain gene

Luca Monaldini, Rosanna Asselta, Stefano Duga, Flora Peyvandi, Kanjaksha Ghosh, Massimo Malcovati, Maria Luisa Tenchini

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Objectives. Afibrinogenemia and hypofibrinogenemia are rare inherited coagulation disorders characterized by hemorrhagic manifestations of variable entity and by plasma fibrinogen deficiency. So far, 57 mutations have been associated with these disorders, and 18 of these are missense mutations. The aim of this study was to characterize the molecular mechanism underlying severe hypofibrinogenemia in a proband from India. Design and Methods. The mutational screening was accomplished by DNA sequencing of the three fibrinogen genes. The mutant protein was expressed in COS-1 cells, and intracellular and secreted mutant fibrinogen was analyzed by means of pulse-chase experiments. Results. A novel homozygous G→A transition in exon 8 (nucleotide position 8017) was found in the proband's fibrinogen Bβ-chain gene. The resulting G434D missense mutation (fibrinogen Mumbai) involves a highly conserved amino acid residue, located in the C-terminal globular D domain. In vitro expression experiments demonstrated intracellular retention of the mutant fibrinogen and marked reduction of its secretion. Interpretation and Conclusions. The G434D substitution causes severe hypofibrinogenemia by impairing fibrinogen secretion. Expression data confirm the importance of Bβ-chain D domain folding in the intracellular processing of fibrinogen.

Original languageEnglish
Pages (from-to)628-633
Number of pages6
JournalHaematologica
Volume91
Issue number5
Publication statusPublished - May 2006

Keywords

  • Congenital afibrinogenemia
  • Fibrinogen Bβ chain
  • Hypofibrinogenemia
  • Missense mutation
  • Protein in vitro expression

ASJC Scopus subject areas

  • Hematology

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