title: Novel mutations in congenital factor XII deficiency.
abstract: Several mutations in factor XII have been reported in patients with factor XII deficiency. Here, we described three mutations in the F12 gene (c. 6635G more than A (p. G259E), c. 6658G more than C (p. R267G) and c. 8489G more than A (p. E521K)) of five patients with congenital FXII deficiency. Among these, two were heterozygous mutations. All five patients had prolonged activated partial thromboplastin time, as well as markedly decreased FXII activity and antigen levels. In vitro studies in transiently transfected HEK 293T cells demonstrated that these mutations significantly lowered the FXII levels in the culture media, but had no impact on transcription. Further protein degradation inhibition experiments with various inhibitors suggested that the three mutants were degraded intracellularly through the proteasome pathway in the pre-Golgi compartment. Moreover, G259E and R267G mutations exhibited dominant negative effects, consistent with the phenotypes observed in the heterozygous carriers. Such dominant negative effects were not due to the dimerization of FXII. Our findings suggest that the three mutations in the F12 gene are the causing reasons for the cross-reactive material-negative FXII deficiencies.
authors.forename: Peipei
authors.initials: P
authors.lastname: Jin
authors.forename: Wenli
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Pediatric Hematology ＆ Oncology Ministry of Health, Pediatric Translational Medicine Institute, 2Department of Pediatric surgery, Shanghai Children\'s Medical Center, 3Departments of Clinical Laboratory, Xinhua Hospital, 4Departments o.
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.forename: Lanbo
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Pediatric Hematology ＆ Oncology Ministry of Health, Pediatric Translational Medicine Institute, 2Department of Pediatric surgery, Shanghai Children\'s Medical Center, 3Departments of Clinical Laboratory, Xinhua Hospital, 4Departments o.
authors.forename: Song
authors.initials: S
authors.lastname: Gu
authors.affiliation: The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, People's Republic of China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.forename: Lisong
authors.initials: L
authors.lastname: Shen
authors.affiliation: Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127 China, moxi@vip.126.com.
authors.forename: Xi
authors.initials: X
authors.lastname: Mo
mesh_terms: D000328:Adult; D002675:Child, Preschool; D005174:Factor XII / Q000235:genetics*; D005175:Factor XII Deficiency / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D005174:Factor XII