International Journal of Hematology (2018) 107:436–441
Genetic analysis of a novel missense mutation (Gly542Ser) with factor
XII deciency in a Chinese patient of consanguineous marriage
· Mingshan Wang
· Yanhui Jin
· Xiaoli Cheng
· Kankan Su
· Lihong Yang
Received: 12 May 2017 / Revised: 14 December 2017 / Accepted: 18 December 2017 / Published online: 30 January 2018
© The Japanese Society of Hematology 2018
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.
Keywords Gene mutation · Factor XII deﬁciency · Genetic analysis · CRM · Expression study
Coagulation factor XII (FXII), a single-chain glyco-protein,
produced by hepatocytes and then secreted into plasma as an
inactive serine protease precursor . The molecular weight
is 80 kDa, composed of 596 amino acid residues . FXII is
the initiator of intrinsic coagulation system. It is converted
to activated FXII (FXIIa) by proteolytic cleavage at the
Arg353-Val354 polypeptide bond, Then, FXIIa converted
factor XI to activated factor XI (FXIa), initiating the rapid
intrinsic coagulation pathway. In addition, it also plays a
vital role in ﬁbrinolysis regulation, complement activation,
bradykinin production and inﬂammation [3–5].
Congenital FXII deﬁciency is an autosomal recessive dis-
ease due to mutations in the FXII gene (F12). It can be clas-
siﬁed as three types: a cross-reacting material (CRM)-neg-
ative group (FXII:Ag cannot be detected), a CRM-positive
group (FXII:Ag is normal), and a CRM-reduced group
(FXII:Ag reduced). Most patients with FXII deﬁciency
demonstrate no signiﬁcant clinical symptoms, while sev-
eral cases present with bleeding, thrombosis or recurrent
abortions [6, 7]. And now several clinical investigations
manifested which was a risk factor for thrombosis . They
are usually detected by chance for a prolonged activated par-
tial thromboplastin time (APTT) on health checkup or pre-
operative screening, which always presents with a decreased
FXII activity (FXII:C) . The molecular mechanism for
FXII deﬁciency has been described in only a few cases so
far [10, 11].
In this paper, we detected a patient with FXII deﬁciency
from a consanguineous marriage family, then studied the
phenotype and genotype of the proband and his families. We
also analyzed the conservative and harm of the mutation by
bioinformatics software and performed a transient in vitro
expression study to explore possible mechanisms responsi-
ble for this deﬁcient phenotype.
* Lihong Yang
Department of Clinical Laboratory, The First Aﬃliated
Hospital of Wenzhou Medical University, Shangcai Village,
Ouhai District, Wenzhou 325000, Zhejiang, China