The natural occurrence of human fibrinogen variants disrupting inter-chain disulfide bonds (A{alpha}Cys36Gly, A{alpha}Cys36Arg and A{alpha}Cys45Tyr) confirms the role of N-terminal A{alpha} disulfide bonds in protein assembly and secretion.

Michel Hanss 1 Catherine Pouymayou Marie-Thérèse Blouch 2, 3 Franck Lellouche Patrick Ffrench Robert Rousson 4 Jean-François Abgrall 3, 5 Pierre-Emmanuel Morange 6 Florence Quélin Philippe De Mazancourt 7
1 Laboratoire d'Hématologie
2 GETBO - Groupe d'Etude de la Thrombose de Bretagne Occidentale
3 Service d'hématologie biologique
4 Laboratoire de Cardiogénétique
5 Génétique moléculaire et génétique épidémiologique
6 NORT - Nutrition, obésité et risque thrombotique
7 Laboratoire de Biochimie
Abstract : Analyses of site-directed fibrinogen mutants expressed in several recombinant models have previously shown that both inter- and intra-chain disulfide bonds are critical for fibrinogen assembly and secretion. Four naturally occurring mutations on AαCys36 and AαCys45 residues are reported here to be associated with decreased fibrinogen levels. This confirms the main role of the AαCys36-BβCys65 and AαCys45-γCys23 disulfide bonds in reaching a normal fibrinogen plasma level. Decreased coagulant/antigen ratios indicate abnormal species secretion in heterozygous subjects which varies between individuals. However, in contrast to overexpression in experimental models, disruption of the AαCys36-BβCys65 disulfide bond did not result in the appearance of Aα-Bβ-γ moieties in vivo. A 188 kDa molecule reacting only with anti Aα and anti Bβ chains was found in the plasma of the AαCys45Tyr variant. Heterozygous carriers of Aα chain mutations usually have normal fibrinogen levels, in contrast to the AαCys36Gly, AαCys36Arg and AαCys45Tyr variants that are shown here to cause hypofibrinogenemia.
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Haematologica, Ferrata Storti Foundation, 2011, 96 (8), pp.1226-30. 〈10.3324/haematol.2010.029801〉
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Contributeur : Ghislaine Calvez <>
Soumis le : mercredi 15 janvier 2014 - 08:41:10
Dernière modification le : mardi 1 mai 2018 - 01:04:50

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Michel Hanss, Catherine Pouymayou, Marie-Thérèse Blouch, Franck Lellouche, Patrick Ffrench, et al.. The natural occurrence of human fibrinogen variants disrupting inter-chain disulfide bonds (A{alpha}Cys36Gly, A{alpha}Cys36Arg and A{alpha}Cys45Tyr) confirms the role of N-terminal A{alpha} disulfide bonds in protein assembly and secretion.. Haematologica, Ferrata Storti Foundation, 2011, 96 (8), pp.1226-30. 〈10.3324/haematol.2010.029801〉. 〈hal-00931165〉

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