Human factor VII deficiency caused by S339C mutation located adjacent to the specificity pocket of the catalytic domain.
This report documents our identification of a novel factor VII (FVII) gene mutation in a Japanese boy with FVII deficiency. The proband's FVII activity was 34% and his FVII antigen level was 40% of normal controls. DNA sequence analysis of the proband's FVII gene identified a C to G point mutation at nucleotide position 10 933 in exon 8, which results in the substitution of Cys (TGC) for Ser339 (TCC). Hinf I digestion results indicate the proband and his mother were heterozygous for the mutation. Both wild-type and mutant FVIIs were transiently expressed in COS-1 cells. FVII levels measured in the culture medium of FVII Ser339Cys mutants were markedly reduced as compared to those of cells with FVII wild-type. The amount of intracellular FVII in FVII Ser339Cys mutants was 80% of that in wild-type. In the wild-type FVII, Ser339 is juxtaposed to Asp338, which is positioned at the bottom of the substrate-binding pocket in the protease domain and located adjacent to FVII Cys340, that forms a disulphide bond with Cys368. We suspect that the creation of a novel unpaired cysteine through this mutation leads to abnormal disulphide bonding during protein folding, thereby reducing the secretion of FVII.
Takamiya
Osamu
O
Department of Medical Technology, School of Allied Medical Sciences, Shinshu University, 3-1-1 Matsumoto Asahi, 390-8621 Japan. itosamu@gipac.shinshu-u.ac.jp
Seta
M
M
Tanaka
K
K
Ishida
F
F
D020134:Catalytic Domain / Q000235:genetics*; D002648:Child; D003001:Cloning, Molecular; D003545:Cysteine / Q000235:genetics; D004252:DNA Mutational Analysis; D005167:Factor VII / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D005168:Factor VII Deficiency / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007564:Japan; D008297:Male; D017354:Point Mutation
D005167:Factor VII; D003545:Cysteine