Residual factor VII activity and different hemorrhagic phenotypes in CRM(+) factor VII deficiencies (Gly331Ser and Gly283Ser).
Two cross-reacting material-positive (CRM(+)) factor VII (FVII) mutations, associated with similar reductions in coagulant activity (2.5%) but with mild to asymptomatic (Gly331Ser, c184 [in chymotrypsin numbering]) or severe (Gly283Ser, c140) hemorrhagic phenotypes, were investigated. The affected glycines belong to structurally conserved regions in the c184 through c193 and c140s activation domain loops, respectively. The natural mutants 331Ser-FVII and 283Ser-FVII were expressed, and in addition 331Ala-FVII and 283Ala-FVII were expressed because 3 functional serine-proteases bear alanine at these positions. The 331Ser-FVII, present in several asymptomatic subjects, showed detectable factor Xa generation activity in patient plasma (0.7% +/- 0.2%) and in reconstituted system with the recombinant molecules (2.7% +/- 1.1%). The reduced activity of recombinant 283Ala-FVII (7.2% +/- 2.2%) indicates that the full function of FVII requires glycine at this position, and the undetectable activity of 283Ser-FVII suggests that the oxydrile group of Ser283 participates in causing severe CRM(+) deficiency. Furthermore, in a plasma system with limiting thromboplastin concentration, 283Ser-FVII inhibited wild-type FVIIa activity in a dose-dependent manner.
Pinotti
Mirko
M
Dipartimento di Biochimica e Biologia Molecolare-CIBF, University of Ferrara, Italy.
Etro
Daniela
D
Bindini
Debora
D
Papa
Maria Luisa
ML
Rodorigo
Giuseppina
G
Rocino
Angiola
A
Mariani
Guglielmo
G
Ciavarella
Nicola
N
Bernardi
Francesco
F
Pinotti
Marko
M
Etro
Dániela
D
Mariani
Guglieuto
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D001483:Base Sequence; D003429:Cross Reactions / Q000235:genetics; D005167:Factor VII / Q000235:genetics* / Q000378:metabolism; D005168:Factor VII Deficiency / Q000235:genetics*; D005260:Female; D006470:Hemorrhage / Q000209:etiology* / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D013329:Structure-Activity Relationship
D005167:Factor VII