Identification of a novel mutation of factor XII gene in a family with coagulation F XII deficiency

Objective: To analyze genetic mutation and molecular pathogenesis in a family affected with inherited coagulation factor XII (F XII) deficiency. Methods: Activated partial thromboplastin time (APTT), F XII procoagulant activity (F XII:C), F XII antigen (F XII:Ag) and other coagulants were measured. For affected members of the family, exons 1-14 and flanking intronic regions of the F XII gene were amplified with polymerase chain reaction (PCR) and sequenced thereafter. Expression plasmids containing mutant F XII cDNA was constructed and transfected into COS7 cells transiently. Expressions of F XII:Ag and F XII:C were analyzed. Results: The proband has manifested a prolonged APTT of 108.1 s (reference range: 27.0-41.0 s). Her husband has a normal APTT. Other members of the family had slightly increased APTT. The F XII:C and F XII:Ag of the proband have both dropped to about 0.01 (reference range: 0.72-1.13). The F XII:C levels of her husband, son, daughter and grandchild were 0.57, 0.24, 0.14, 0.16, respectively. And the F XII:Ag levels in her husband, son, daughter and grandchild were 0.55, 0.27, 0.15, 0.21, respectively. The proband and her daughter have both carried a heterozygous deletional mutation 6800-6808delAGCTGGGAG (6800-6808del9bp) in exon 9. For the promoter region of the F XII gene, the genotypes of the proband, her son, daughter and grandchild was TT, whilst that of her husband was CT. Expression study has shown that, whilst the mutant F XII protein has accumulated in the cells similar to wild-type protein, its secretion has reduced approximately by half. Conclusion: A novel deletional mutation 6800-6808del9bp has been identified in the F XII gene. Although mutant F XII protein can still accumulate in cells, its secretion has become insufficient. The 6800-6808del9bp mutation and 46T/T have both contributed to the pathogenesis of F XII deficiency in the family, but may have not been the sole cause.