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

Summary

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 dys-functional type of FXII with a partial defect (0.41–0.45) in prekallikrein cleavage activity.

Keywords

Amino acid substitution - catalytic domain - chromogenic substrate - F12 haplotype - intrinsic coagulation pathway

• References

• 1 Cool DE, Edgell C-J, Louie GV. et al. Characterization of human blood coagulation factor XII cDNA. Prediction of the primary structure of β-factor XIIa. J Biol Chem 1985; 260: 13666-13676.
• 2 Dunn JT, Silverberg M, Kaplan AP. The cleavage and formation of activated human Hageman factor by autodigestion and by kallikrein. J Biol Chem 1982; 257: 1779-1784.
• 3 Wuepper KD, Cochrane CG. Plasma prekallikrein: Isolation, characterization, and mechanism of action. J Exp Med 1972; 135: 1-20.
• 4 Schmaier AH and LaRusch G. Factor XII: New life for an old protein. Thromb Haemost 2010; 104: 915-918.
• 5 Cool DE, MacGillivray RTA. Characterization of the human blood coagulation factor XII gene: Intron/exon gene organization and analysis of the 5’- flanking region. J Biol Chem 1987; 262: 13662-13673.
• 6 Human Gene Mutation Database. Available at: http://www.hgmd.cf.ac.uk/ac/all.php
• 7 Feng Y, Ye X, Pang Y, Dai J. et al. A novel mutation in a patient with congenital coagulation factor XII deficiency. Chinese Med J 2008; 121: 1241-1244.
• 8 Lombardi AM, Bortoletto E, Scarparo P, Scapin M. et al. Genetic study in patients with factor XII deficiency: a report of three new mutations exon 13(Q501STOP), exon 14 (P547L) and –13>T promoter region in three compound heterozygotes. Blood Coagul Fibrinolysis 2008; 19: 639-643.
• 9 Miyata T, Kawabata S, Iwanaga S. et al. Coagulation factor XII (Hageman factor) Washington D.C.: Inactive factor XIIa results from Cys-571→Ser substitution. Proc Natl Acad Sci USA 1989; 86: 8319-8332.
• 10 Wuillemin WA, Furlan M, Stricker H. et al. Functional characterization of a variant factor XII (F XII Locarno) in a cross reacting material positive F XII deficient plasma. Thromb Haemost 1992; 67: 219-225.
• 11 Schloesser M, Zeerleder S, Lutze G. et al. Mutations in the human factor XII gene. Blood 1977; 90: 3967-3977.
• 12 Kondo S, Tokunaga F, Kawano S. et al. Factor XII Tenri, a novel cross-reacting material negative factor XII deficiency, occurs through a proteasome-mediated degradation. Blood 1999; 93: 4300-4308.
• 13 Kanaji T, Okamura T, Osaki K. et al. A common genetic polymorphism (46 C to T substitution) in the 5’-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998; 91: 2010-2014.
• 14 Saito H, Scott JG, Movat HZ. et al. Molecular heterogeneity of Hageman trait (factor XII deficiency). Evidence that two of 49 subjects are cross-reacting material positive (CRM⁺). J Lab Clin Med 1979; 94: 256-265.
• 15 Berretini M, Lammle B, Ciavarella G. et al. Functional and immunological studies of abnormal factor XII in a cross reacting material positive (CRM⁺) factor XII deficiency. Thromb Haemost 1981; 54: 120 (Abstract).
• 16 Takahashi I, Saito H. A rapid purification with high recovery of factor XII (Hageman factor) on immunoaffinity column: Application to an abnormal clotting factor XII (Factor XII Toronto). J Biochem 1988; 103: 641-643.
• 17 Wuillemin WA, Furlan HM, Lämmle B. Functional characterization of an abnormal factor XII molecule (F XII Bern). Blood 1991; 78: 997-1004.
• 18 Hovinga JK, Schaller J, Stricker H. et al. Coagulation factor XII Locarno: The functional defect is caused by the amino acid substitution Arg353→Pro leading to loss of a kallikrein cleavage site. Blood 1994; 84: 1173-1181.
• 19 Hoem N-O, Johannesen S, Briseid K. Assay of factor XII in human plasma using prekallikrein or the chromogenic peptide S-2222 as substrates – significance of the functional state of plasma kallikrein. Thromb Res 1989; 54: 197-205.