title: Afibrinogenemia resulting from homozygous nonsense mutation in A alpha chain gene associated with multiple thrombotic episodes.
abstract: Congenital afibrinogenemia is a rare disorder characterized by the absence in circulating fibrinogen, a hexamer composed of two sets of three polypeptides (Aalpha, Bbeta and gamma). Although predisposition to thrombosis is a well known feature of dysfibrinogenemia, the relatively frequent thrombotic manifestations seen in congenital afibrinogenemia are puzzling. We herein report a mutational analysis of a young afibrinogenemic man from Turkey with multiple thrombo-embolic events involving both arteries and veins. Purified DNAs of the propositus was used for amplification by polymerase chain reaction of all the exons of the A subunit gene with primers allowing the analysis of the intron-exon boundaries. Analysis of the genes coding for the three fibrinogen chains of the propositus found a homozygous G to A transition in the exon 5 of the A alpha chain gene (g.g4277a; access number gi458553). The TGG to TGA codon change predicts a homozygous W315X in the A alpha chain (p.W334X when referring to the translation initiation codon). Both parents and his brother were found to carry this heterozygous mutation. This is the first report of a patient homozygous for this rare mutation associated with afibrinogenemia. Our patient was free of known risk factors as well as diseases associated with thrombosis including atherosclerosis, vasculitis, Buerger's disease, and it seems therefore probable that afibrinogenemia itself might have contributed to both arterial and venous thrombosis.
authors.affiliation: Gulhane Military School of Medicine, Division of Rheumatology, Ankara, Turkey. isimsek@gata.edu.tr
authors.forename: Ismail
authors.initials: I
authors.lastname: Simsek
authors.forename: Philippe
authors.initials: P
authors.lastname: de Mazancourt
authors.forename: Marie-Hèléne
authors.initials: MH
authors.lastname: Horellou
authors.forename: Hakan
authors.initials: H
authors.lastname: Erdem
authors.forename: Salih
authors.initials: S
authors.lastname: Pay
authors.forename: Ayhan
authors.initials: A
authors.lastname: Dinc
authors.forename: Meyer Michel
authors.initials: MM
authors.lastname: Samama
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D018389:Codon, Nonsense; D003241:Consanguinity; D005340:Fibrinogen / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013927:Thrombosis / Q000209:etiology*
chemical_list: D018389:Codon, Nonsense; C464794:fibrinogen Aalpha; D005340:Fibrinogen