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

Abstract

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.

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

“…This observation indicates that c.1681C>A (p.Gly542Ser) mutation could be quite common among the Taiwanese population. These three patients also had a similar FXII antigen level of around 40% which is also different from Zou’s report [ 19 ]. We are not sure about the actual cause of the difference between Zou’s and our observation.…”

“…The latter mutation has not been reported before. Unlike Zou’s report [ 19 ], our patients II, III and IV, harboring the same homozygous c.1681C>A (p.Gly542Ser) mutation, did not come from consanguineous marriages and were not related to each other. This observation indicates that c.1681C>A (p.Gly542Ser) mutation could be quite common among the Taiwanese population.…”

“…One of them (patient V) had compound heterozygous mutations of F12 , c.1681C>A (p.Gly542Ser) and c.1556T>A (p.Leu500Gln). The former mutation was previously reported by Zou et al [ 19 ] from a Chinese consanguineous family. The latter mutation has not been reported before.…”

A Chinese host genetic study discovered type I interferons and causality of cholesterol levels and WBC counts on COVID-19 severity

“…Specifically, the rs1801020 ( F12 )-APTT association was previously identified in GWAS analysis from the BioBank Japan Project (BBJ), one of the largest East Asian biobanks with over 160,000 subjects 26 . The gene F12 encodes coagulation factor XII that participates in the initiation of blood coagulation and mutation of F12 will cause prolonged coagulation time and poor thromboplastin production 27 . The rs56393506 ( LPA )-LpA association was previously identified by GWAS in European population with over 13,781 individuals 28 but not in Asian population based on genomic studies.…”

A Chinese host genetic study discovered IFNs and causality of laboratory traits on COVID-19 severity

“…Specifically, the rs1801020 (F12)-APTT association was previously identified in GWAS analysis from the BioBank Japan Project (BBJ), one of the largest EAS biobanks with over 160,000 subjects (Kanai et al, 2018). The gene F12 encodes coagulation factor XII that participates in the initiation of blood coagulation, and mutation of F12 will cause prolonged coagulation time and poor thromboplastin production (Zou et al, 2018). The rs56393506 (LPA)-LpA association was previously identified by GWAS in the EUR population with over 13,781 individuals (Mack et al, 2017) but not in the EAS population based on genomic studies.…”