Fibrinogens Kosai and Ogasa: Bbeta15Gly-->Cys (GGT-->TGT) substitution associated with impairment of fibrinopeptide B release and lateral aggregation.
We found two heterozygous dysfibrinogenemias, designated fibrinogen Kosai and fibrinogen Ogasa. Kosai was associated with arteriosclerosis obliterans but Ogasa showed no bleeding or thrombotic tendencies. The plasma fibrinogen concentrations from the two propositi (Ogasa and Kosai) were much lower when determined by the thrombin-time method (0.94 and 1.06 g L(-1), respectively) than when determined by the immunological method (2.87 and 2.72 g L(-1), respectively). We performed DNA sequencing and functional analyses to clarify the relationship between the structural and functional abnormalities. Genetic analysis of PCR-amplified DNA from the propositi identified the heterozygous substitution Bbeta15Gly-->Cys (GGT-->TGT). Western blotting analysis of purified fibrinogen revealed the existence of albumin-fibrinogen complexes. Functional analyses indicated that compared with the normal control, the propositi's fibrinogen released only half the normal amount of fibrinopeptide B and showed markedly impaired polymerization. In addition, the observation of thinner fibers in fibrin clots (by scanning electron microscopy) indicated markedly defective lateral aggregation in the variant fibrinogens. The impaired functions may be due to the substitution of Cys for Bbetao15Gly plus the existence of some additional disulfide-bonded forms.
Hirota-Kawadobora
M
M
Central Clinical Laboratory, Shinshu University Hospital, Matsumoto, Nagano, Japan.
Terasawa
F
F
Yonekawa
O
O
Sahara
N
N
Shimizu
E
E
Okumura
N
N
Katsuyama
T
T
Shigematsu
H
H
D000328:Adult; D000347:Afibrinogenemia / Q000097:blood* / Q000235:genetics*; D019943:Amino Acid Substitution; D012103:Batroxobin / Q000494:pharmacology; D005260:Female; D015241:Fibrinogens, Abnormal / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D005345:Fibrinopeptide B / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D017354:Point Mutation; D013917:Thrombin / Q000494:pharmacology
D015241:Fibrinogens, Abnormal; D005345:Fibrinopeptide B; D012103:Batroxobin; D013917:Thrombin