A new type of Ser substitution for gamma Arg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly.
A new type of substitution, Arg to Ser at gamma275, has been found in a heterozygous dysfibrinogen derived from a 23-year-old woman with no major bleeding or thrombosis. By sequence analyses of the affected gamma-chain and its gene. we found a single amino acid substitution of gamma Arg-275 to Ser in an aberrant gamma (274-302) residue peptide isolated from lysyl endopeptidase-digests of the patient's fibrinogen. In agreement with this amino acid substitution, we identified a single nucleotide exchange of A for C at position 5728 in the gamma-chain gene creating a codon (AGC) encoding Ser instead of the codon (CGC) encoding Arg at position gamma 275. Like two other known types of mutants with a His or Cys substitution at this position, the functional abnormality was characterized by delayed fibrin polymerization, most likely due to impaired abutting of two D domains of adjacent fibrin monomers in the same strand of fibrin protofibrils. The structural derangement that affects the D:D association may not be so severe as compared with those of Cys and His mutants, possessing an additional disulfide-linked Cys molecule and an imidazole ring at the mutation site, respectively.
Division of Hemostasis and Thrombosis Research, Institute of Hematology, Jichi Medical School, Tochigi-Ken, Japan.
J
J
Mimuro
Y
Y
Kawata
K
K
Niwa
S
S
Muramatsu
S
S
Madoiwa
H
H
Takano
T
T
Sugo
Y
Y
Sakata
T
T
Sugimoto
K
K
Nose
M
M
Matsuda
D000328:Adult; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D001777:Blood Coagulation; D005260:Female; D005337:Fibrin / Q000378:metabolism*; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017354:Point Mutation; D012694:Serine / Q000235:genetics
D012694:Serine; D005337:Fibrin; D005340:Fibrinogen; D001120:Arginine