title: Identification of a novel splicing mutation in the fibrinogen gamma chain gene leading to dysfibrinogenaemia in a Chinese pedigree.
abstract: Congenital dysfibrinogenaemia is a rare disease characterised by inherited abnormality in the fibrinogen molecule, leading to functional defects. In this study, we investigated the molecular basis of dysfibrinogenaemia in a Chinese pedigree. Functional fibrinogen of venous blood samples was measured by Clauss method, and the antigens of fibrinogen in plasma were measured by immunoturbidimetry assay. All the exons and exon-intron boundaries of the three fibrinogen genes were analysed by direct sequencing. Fibrinogen electrophoresis, fibrinogen clottability measurement, fibrin polymerisation measurement, and electron microscopy scanning were also used in this study. The proband showed prolonged thrombin time, prolonged reptilase time, reduced fibrinogen activity level and normal plasma fibrinogen antigen. The sequencing results of the proband revealed a novel heterozygous IVS9+1delG mutation of FGG gene, which could also be called FGG p.Val434Serfs29. The same results were also found in her mother, sister and daughter. Both thrombin-induced fibrin polymerisation and reptilase induced fibrin polymerisation were significantly impaired compared to normal control. Fibrinogen clottability measurement showed that only about 38.7% molecules of plasma fibrinogen of the proband were involved in the clot formation. Scanning electron microscopy revealed that the proband's average fibre diameters (159 ± 36 nm; n = 100) were found to be significantly thicker than the control's diameter (108 ± 21 nm; n = 100) (p<0.001). The fibrin clot of the proband showed irregular structure and highly branched fibres. We conclude that the mutation is responsible for the proband's dysfibrinogenaemia and clinical symptoms.
authors.affiliation: 1Stem Cell Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang Province 2Clinical Laboratory Department, No.3 People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 3Clinical Laboratory Department, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 4Division of Thrombosis and Hemostasis, Shanghai Institute of Hematology, Shanghai, China *these authors contributed equally to this work and should be considered as co-first authors.
authors.forename: Dandan
authors.initials: D
authors.lastname: Huang
authors.forename: Huayun
authors.initials: H
authors.lastname: Chen
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Hu
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.forename: Hongli
authors.initials: H
authors.lastname: Wang
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000235:genetics*; D044466:Asian People; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010375:Pedigree; D012326:RNA Splicing; D013918:Thrombin Time
chemical_list: D005340:Fibrinogen