Factor XII Osaka: Abnormal factor XII with partially defective prekallikrein cleavage activity

Abstract

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.

A novel missense mutation in the factor XII gene in a litter of cats with factor XII deficiency

“…In human FXII deficiency, a mutation which leads to amino acid change from glycine to glutamic acid at codon 531 (p.G531E) has been reported [5]. This mutation corresponds to the position of the feline p.G544A mutation identified in the present study.…”

“…The p.G531E mutant protein in patient plasma is detectable with anti-FXII antibodies, however, its procoagulant activity is reduced. The presence of a circulating but dysfunctional coagulation factor protein variant is referred to as cross-reactive material (CRM)-positive [5]. In the present study, we could not obtain a feline reactive anti-FXII antibody thereby precluding direct measurement of the amount of plasma FXII antigen in circulation.…”

The prevalence of heterozygous F12 mutations in Chinese population and its relevance to incidents of thrombosis

“…The FXII mutation Ala343Pro is characterized by inconsistent decrease of FXII clotting activity and antigen level in plasma. First identified in Japanese by Iijima, K.et [ 19 ], Ala343Pro has different prevalences among populations, and is overrepresented in East Asian races according to 1000 genome project. Animal studies suggested that FXII did not contribute to the physiological hemostasis, instead, it played a critical role in the pathological thrombosis formation.…”

Novel mutations in congenital factor XII deficiency

“…As of December 2014, a total of 44 FXII mutations have been reported worldwide, including point mutations (missense mutations, nonsense mutations), splice site mutations, deletions and insertions. Several investigators have described the molecular basis of congenital FXII deficiency (9)(10)(11)(12)(13)(14)(15). Most mutations in the F12 gene identified in FXII deficiency patients usually result in the lack of immunologically detectable FXII proteins, a kind of so-called cross-reactive material (CRM)-negative deficiency.…”