Human Molecular Genetics Advance Access originally published online on September 29, 2005
Human Molecular Genetics 2005 14(21):3271-3280; doi:10.1093/hmg/ddi360
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Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia
1Department of Genetic Medicine and Development, 2Department of Cell Physiology and Metabolism, 3Department of Structural Biology and Bioinformatics, Swiss Institute of Bioinformatics, University Medical Centre, 1211 Geneva 4, Switzerland, 4Division of Angiology and Hemostasis, University Hospital, 1211 Geneva 4, Switzerland and 5SBC Lab AG, 8185 Winkel, Switzerland
* To whom correspondence should be addressed at: Department of Genetic Medicine and Development, University Medical Centre, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Tel: +41 223795655; Fax: +41 223795706; Email: marguerite.arbez{at}medecine.unige.ch
Received June 28, 2005; Revised August 15, 2005; Accepted September 13, 2005
Congenital afibrinogenemia is a rare bleeding disorder characterized by the absence in circulation of fibrinogen, a hexamer composed of two sets of three polypeptides (A
, Bß and 
). Each polypeptide is encoded by a distinct gene, FGA, FGB and FGG, all three clustered in a region of 50 kb on 4q31. A subset of afibrinogenemia mutations has been shown to specifically impair fibrinogen secretion, but the underlying molecular mechanisms remained to be elucidated. Here, we show that truncation of the seven most C-terminal residues (R455–Q461) of the Bß chain specifically inhibits fibrinogen secretion. Expression of additional mutants and structural modelling suggests that neither the last six residues nor R455 is crucial per se for secretion, but prevent protein misfolding by protecting hydrophobic residues in the ßC core. Immunofluorescence and immuno-electron microscopy studies indicate that secretion-impaired mutants are retained in a pre-Golgi compartment. In addition, expression of Bß, and angiopoietin-2 chimeric molecules demonstrated that the ßC domain prevents the secretion of single chains and complexes, whereas the C domain allows their secretion. Our data provide new insight into the mechanisms accounting for the quality control of fibrinogen secretion and confirm that mutant fibrinogen retention is one of the pathological mechanisms responsible for congenital afibrinogenemia.
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