Identification of Genetic Defects Underlying FXII Deficiency in Four Unrelated Chinese Patients

Abstract

Congenital factor XII (FXII) deficiency is a rare autosomal recessive disorder, characterized by a great variability in its clinical manifestations. In this study, we screened for mutations in the F12 gene of 4 unrelated patients with FXII coagulant activity <10% of that of normal human plasma. To investigate the molecular defects in these FXII-deficient patients, we performed FXII mutation screening. By sequencing all coding exons as well as flanking intronic regions of the F12 gene, 6 different mutations, including 3 missense mutations (Gly341Arg, Glu502Lys and Gly542 Ser), 1 insertion (7142insertC) and 2 deletions (5741-5742 delCA and 6753-6755delACA), were identified on the F12 gene. Three of them (Gly341Arg, 5741-5742delCA and 6753-6755delACA) are reported here for the first time. Computer-based algorithms predicted these missense mutations to be deleterious. This study has increased our knowledge of the mutational spectrum underlying FXII deficiency.

Compound heterozygous mutations Glu502Lys and Met527Thr of the FXII gene in a patient with factor XII deficiency

“…In addition, expect the proband and his father were heterozygotes 46CT, the other three members all took 46CC genotype, which indicated that the 46CT polymorphism has no significant effect on the reduction of FXII:C in this family. There are no other factors contribute to the activity and antigen reduction of FXII, and the reduced degree of FXII:C and FXII:Ag in the compound heterozygous FXII deficiency is consistent with many previous reports [15,16]. Therefore, we initially believe that the compound heterozygous mutations Glu502Lys and Met527Thr were responsible for the reduction of FXII:C and FXII:Ag.…”

“…FXII may be an essential element of thrombosis in vivo [14]. Many reported cases of FXII deficiency have no thrombosis, which is consistent with animal studies [4,10,15,16]. These findings have generated new interest in FXII because it affects thrombosis without affecting hemostasis, so FXII may be the perfect target for the development of new antithrombotic drugs [17].…”

“…In combination with Figure 1, we could see that the compound heterozygous mutations (Glu502Lys and Met527Thr) of proband were inherited from his father and mother, respectively, and the mode of its inheritance is consistent with the common autosomal recessive inheritance pattern of patients with hereditary FXII deficiency. This is the first report of Met527Thr, and Glu502Lys has been reported [15,16]. The results of prediction are as above table, the meanings of scores are as follows: 1.…”

Characterization of congenital factor XII deficiency in Taiwanese patients: identification of one novel and one common mutation

“…However, Leu500 and Gly542 were conserved in trypsin-like proteins, but Glu502 was not [ 22 ]. The p.Glu502Lys [ 23 ], and p.Gly542Ser FXII gene [ 18 ] mutations have been reported previously.

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Double Heterozygous Mutations (Cys247Tyr and 252delAsn) Cause Factor XII Deficiency in a Chinese Family

“…This is the first report of Cys247Tyr, and 252delAsn has been reported. 14 To further prove the adverse effect of Cys247Tyr and 252delAsn, we analyzed their conservatism and the possible effects on the protein. It turns out that in homologous species, Cys247 and Asn252 were highly conserved sites, both of which were considered to be important functional sites of FXII.…”