title: Fibrinogen Mumbai: intracellular retention due to a novel G434D mutation in the Bbeta-chain gene.
abstract: OBJECTIVE
  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.
  
  
  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 Bbeta-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.
  
  
  CONCLUSIONS
  The G434D substitution causes severe hypofibrinogenemia by impairing fibrinogen secretion. Expression data confirm the importance of Bbeta-chain D domain folding in the intracellular processing of fibrinogen.
authors: Department of Biology and Genetics for Medical Sciences, University of Milan, Milan, Italy. stefano.duga@unimi.it
authors: Luca
authors: L
authors: Monaldini
authors: Rosanna
authors: R
authors: Asselta
authors: Stefano
authors: S
authors: Duga
authors: Flora
authors: F
authors: Peyvandi
authors: Kanjaksha
authors: K
authors: Ghosh
authors: Massimo
authors: M
authors: Malcovati
authors: Maria Luisa
authors: ML
authors: Tenchini