title: 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.
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.
authors: Laboratoire d’Hématologie, CBPE, Hospices Civils de Lyon, Lyon, France.
authors: Michel
authors: M
authors: Hanss
authors: Catherine
authors: C
authors: Pouymayou
authors: Marie-Thérèse
authors: MT
authors: Blouch
authors: Franck
authors: F
authors: Lellouche
authors: Patrick
authors: P
authors: Ffrench
authors: Robert
authors: R
authors: Rousson
authors: Jean-François
authors: JF
authors: Abgrall
authors: Pierre-Emmanuel
authors: PE
authors: Morange
authors: Florence
authors: F
authors: Quélin
authors: Philippe
authors: P
authors: de Mazancourt
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic; D011487:Protein Conformation
chemical_list: D004220:Disulfides; D005340:Fibrinogen