Genetic analysis of a novel missense mutation (Gly542Ser) with factor XII deficiency in a Chinese patient of consanguineous marriage.

Coagulation factor XII deficiency is a rare autosomal recessive disorder, which could be found in a consanguineous family. We studied a Chinese family in which the activated partial thromboplastin time (APTT) of the proband had clearly prolonged up to 101.7 s, associated with low FXII activity of 3% and FXII antigen < 1%. To analyze the gene mutation in this FXII-deficient patient, we performed FXII mutation screening, and analyzed the DNA sequence of the F12 gene. A ClustalX-2.1-win and four online bioinformatics software services were used to study the conservatism and effects of the mutation. A transient in vitro expression study was performed to elucidate the possible pathological mechanism. Sequence analysis revealed a homozygous c.1681 G > A point mutation in exon 14, causing a novel Gly542Ser mutation in the catalytic domain. The results of the conservatism and bioinformatics analyses both indicated that the mutation likely affects the function of the protein. Additional expression studies in COS-7 cells showed that the antigen level of mutant FXII (FXII-Gly542Ser) was lower than wild type in culture medium, whereas the corresponding level of FXII antigen in cell lysates was equivalent. These results suggest that the Gly542Ser mutation causes FXII deficiency through intracellular degradation.