Factor XII Osaka: abnormal factor XII with partially defective prekallikrein cleavage activity.
A healthy Japanese male had reduced factor XII (FXII) activity (35%) in contrast to normal antigen levels (81%). The F12 of this proband had a 9775G to C mutation in exon 10 and an 11276G to A mutation in exon 13 that resulted in two amino acid substitutions of Ala324Pro (GCG→CCG) in the proline-rich connecting region and Gly531Glu (GGG→GAG) near the active Ser544 in the catalytic domain. His father had the nucleotide 46T/T and a heterozygous 9775G/C mutation. The FXII activity (32%) and antigen level (38%) of the father were about half that of normal individuals with 46T/T, suggesting a heterozygous cross reacting material (CRM)-negative deficiency. His mother had a 46C/T and heterozygous 11276G/A mutation, and 80% FXII activity was incompatible with the corresponding antigen level (125%), suggesting a heterozygous CRM-positive deficiency. The substitution of Ala324Pro probably caused the CRM-negative mutation and the Gly531Glu caused the CRM-positive mutation. We developed three methods based on chromogenic substrates to assay the distinct functions of FXII, namely its autoactivation on a negatively charged surface, activation by kallikrein cleavage and the prekallikrein cleavage activity of FXIIa. The ratios of autoactivated FXIIa/FXII antigen (0.80-1.10) and of kallikrein-induced FXIIa/FXII antigen (0.86-1.00) in plasma from the proband were within normal ranges, whereas those of FXIIa-induced kallikrein/FXII antigen were reduced to 0.41-0.45. In conclusion, the 9775G to C and 11276G to A mutations of F12 led to a CRM-negative and -positive FXII deficiency, and the F12 with 11276A produced a dysfunctional type of FXII with a partial defect (0.41-0.45) in prekallikrein cleavage activity.
Department of Pathobiological Science and Technology, School of Health Science, Faculty of Medicine, Tottori University, Yonago, Japan. kenijima@med.tottori-u.ac.jp
Kenji
K
Iijima
Yuya
Y
Arakawa
Yuya
Y
Sugahara
Michiko
M
Matsushita
Yuki
Y
Moriguchi
Hisashi
H
Shimohiro
Mayumi
M
Nakagawa
D000328:Adult; D001777:Blood Coagulation; D020134:Catalytic Domain; D005091:Exons; D005174:Factor XII / Q000235:genetics*; D005175:Factor XII Deficiency / Q000097:blood; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007610:Kallikreins / Q000737:chemistry; D008297:Male; D009154:Mutation; D010314:Partial Thromboplastin Time; D016133:Polymerase Chain Reaction / Q000379:methods; D017422:Sequence Analysis, DNA
D005174:Factor XII; D007610:Kallikreins