title: Heterozygous Bβ-chain C-terminal 12 amino acid elongation variant, BβX462W (Kyoto VI), showed dysfibrinogenemia.
abstract: A heterozygous patient with dysfibrinogenemia with slight bleeding and no thrombotic complications was diagnosed with fibrinogen Kyoto VI (K-VI). To elucidate the genetic mutation(s) and characterize the variant protein, we performed the following experiments and compared with identical and similar variants that have already been reported. The proposita's PCR-amplified DNA was analyzed by sequencing and her purified plasma fibrinogen underwent SDS-PAGE followed by immunoblotting, fibrin polymerization, and scanning electron microscopic observation of fibrin clot and fibers. Sequence analyses showed that K-VI fibrinogen substituted W (TGG) for terminal codon (TAG), resulting in 12 amino acid elongation 462-473 (WSPIRRFLLFCM) in the Bβ-chain. Protein analyses indicated that the presence of some albumin-binding variant fibrinogens and a dimeric molecule of variant fibrinogens reduced fibrin polymerization, with a thinner fiber and aberrant fibrin network. These results are almost the same as for the identical variant of Magdeburg, however, different from the similar variant of Osaka VI [12 amino acid elongation 462-473 (KSPIRRFLLFCM) in the Bβ-chain] in the presence of variant forms and clot structure. We speculate the side-chain difference at 462 residues, W in K-VI, K in Osaka VI, and/or the difference in the presence of disulfide bridged forms of variant fibrinogens, led to the notable difference in the fibrin bundle network. Although a strong evolutional and structural association between Bβ-chain and γ-chain molecules is established, the corresponding recombinant 15 residue elongation variants of the fibrinogen γ-chain showed reduced assembly and secretion.
authors: Department of Biomedical Laboratory Sciences, School of Health Sciences, Shinshu University, Matsumoto, Japan. nobuoku@shinshu-u.ac.jp
authors: Nobuo
authors: N
authors: Okumura
authors: Fumiko
authors: F
authors: Terasawa
authors: Yuka
authors: Y
authors: Takezawa
authors: Masako
authors: M
authors: Hirota-Kawadobora
authors: Tohru
authors: T
authors: Inaba
authors: Naohisa
authors: N
authors: Fujita
authors: Masazumi
authors: M
authors: Saito
authors: Mitsutoshi
authors: M
authors: Sugano
authors: Takayuki
authors: T
authors: Honda
mesh_terms: D000347:Afibrinogenemia / Q000097:blood / Q000235:genetics*; D000596:Amino Acids; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged
chemical_list: D000596:Amino Acids; D005340:Fibrinogen