1.A case of congenital afibrinogenemia.
Hee Soo KIM ; Kook In PARK ; Ran NAMGUNG ; Chul LEE ; Dong Gwan HAN ; Kir Young KIM ; Hyun Sook KIM
Korean Journal of Perinatology 1992;3(2):99-103
No abstract available.
Afibrinogenemia*
2.Research progress on hereditary fibrinogen abnormalities.
Ning-Jiang OU ; Min-Zhong TANG
Journal of Experimental Hematology 2014;22(4):1188-1192
As the most abundant component of coagulation system, fibrinogen not only takes part in clotting, but also works as one of acute phase proteins, which participates in many physiological and pathophysiological processes. Studies of fibrinogen abnormalities contribute to understand the molecular basis of disorders of fibrinogen protein function and metabolism, caused mainly by gene mutation, commonly associated with bleeding, thrombophilia, or both. Diseases affecting fibrinogen could be classified to the acquired or inherited disease. In this review, the research progress on the molecular basis, possible action mechanism of the hereditary fibrinogen abnormalities and its clinical research are summarized.
Afibrinogenemia
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genetics
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Blood Coagulation Disorders
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genetics
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Humans
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Mutation
3.Congenital Fibrinogen Deficiency Caused by Novel FGG Gene Mutation.
Tian-Tian WANG ; Jing-Ru SHAO ; Jie WANG ; Yan CHENG ; Xue-Qin ZHANG ; Yun-Hai FANG ; Cheng-Fang YAO ; Xin-Sheng ZHANG
Journal of Experimental Hematology 2021;29(2):586-590
OBJECTIVE:
To detect and analyze coagulation related indexes and genotypes of a patient with congenital fibrinogen deficiency and his family members, and to investigate the possible molecular pathogenesis.
METHODS:
Four peripheral blood samples (proband and 3 family members) were collected and the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg), D-Dimer and eight coagulation factor indicators were detected. All exons and flanking sequences of the FGA, FGB, and FGG genes encoding the three peptide chains of fibrinogen were sequenced and analyzed by bioinformatics.
RESULTS:
Among the eight coagulation factors of the proband and the elder sister, F Ⅴ and F Ⅷ were slightly higher, TT was significantly prolonged, and Fg was significantly reduced. Sequencing results showed that c.901C>T heterozygous mutation existed in the FGG gene. Bioinformatics analysis showed that the mutation changed the original protein structure and reduced the number of hydrogen bonds.
CONCLUSION
The fibrinogen gamma chain c.901C>T heterozygous mutation is the main cause of congenital fibrinogen deficiency in this family. This mutation is reported for the first time at home and abroad.
Afibrinogenemia/genetics*
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Aged
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Fibrinogen/genetics*
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Heterozygote
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Humans
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Mutation
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Pedigree
4.Phenotype and genotype analyses of two pedigrees with inherited fibrinogen deficiency.
Kai Qi JIA ; Zheng Xian SU ; Hui Lin CHEN ; Xiao Yong ZHENG ; Man Lin ZENG ; Ke ZHANG ; Long Ying YE ; Li hong YANG ; Yan Hui JIN ; Ming Shan WANG
Chinese Journal of Hematology 2023;44(11):930-935
Objective: To analyze the phenotype and genotype of two pedigrees with inherited fibrinogen (Fg) deficiency caused by two heterozygous mutations. We also preliminarily probed the molecular pathogenesis. Methods: The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and plasma fibrinogen activity (Fg∶C) of all family members (nine people across three generations and three people across two generations) were measured by the clotting method. Fibrinogen antigen (Fg:Ag) was measured by immunoturbidimetry. Direct DNA sequencing was performed to analyze all exons, flanking sequences, and mutated sites of FGA, FGB, and FGG for all members. Thrombin-catalyzed fibrinogen polymerization was performed. ClustalX 2.1 software was used to analyze the conservatism of the mutated sites. MutationTaster, PolyPhen-2, PROVEAN, SIFT, and LRT online bioinformatics software were applied to predict pathogenicity. Swiss PDB Viewer 4.0.1 was used to analyze the changes in protein spatial structure and molecular forces before and after mutation. Results: The Fg∶C of two probands decreased (1.28 g/L and 0.98 g/L, respectively). The Fg∶Ag of proband 1 was in the normal range of 2.20 g/L, while it was decreased to 1.01 g/L in proband 2. Through genetic analysis, we identified a heterozygous missense mutation (c.293C>A; p.BβAla98Asp) in exon 2 of proband 1 and a heterozygous nonsense mutation (c.1418C>G; p.BβSer473*) in exon 8 of proband 2. The conservatism analysis revealed that Ala98 and Ser473 presented different conservative states among homologous species. Online bioinformatics software predicted that p.BβAla98Asp and p.BβSer473* were pathogenic. Protein models demonstrated that the p.BβAla98Asp mutation influenced hydrogen bonds between amino acids, and the p.BβSer473* mutation resulted in protein truncation. Conclusion: The dysfibrinogenemia of proband 1 and the hypofibrinogenemia of proband 2 appeared to be related to the p.BβAla98Asp heterozygous missense mutation and the p.BβSer473* heterozygous nonsense mutation, respectively. This is the first ever report of these mutations.
Humans
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Afibrinogenemia/genetics*
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Codon, Nonsense
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Pedigree
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Phenotype
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Fibrinogen/genetics*
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Genotype
5.Spleen Rupture in Congenital Afibrinogenemia.
Dae Yeon KIM ; Seong Chul KIM ; In Koo KIM
Journal of the Korean Association of Pediatric Surgeons 1999;5(2):137-140
Congenital afibrinogenemia is a rare disorder that refers to a congenital lack of production of fibrinogen, a key component of the hemostatic system. Bleeding manifestations of congenital afibrinogenemia vary in severity from mild to catastrophic. This is a case report of splenic rupture occurred in an eight-year-old boy with congenital afibrinogenemia. A conservative treatment was carried out with perfusion of cryoprecipitate and purified virally inactivated fibrinogen concentrates and splenectomy was avoided.
Afibrinogenemia*
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Fibrinogen
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Hemorrhage
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Humans
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Male
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Perfusion
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Rupture*
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Spleen*
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Splenectomy
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Splenic Rupture
6.Clinical and genetic analysis of 8 Chinese pedigrees with inherited dysfibrinogenemia.
Minghua JIANG ; Xiaoou WANG ; Kuangyi SHU ; Weiyan JIANG ; Ying HUANG ; Ying LIN ; Shanshan LI ; Yunliang HU
Chinese Journal of Medical Genetics 2014;31(2):134-139
OBJECTIVETo analyze clinical manifestation and genetic mutations in 8 Chinese pedigrees featuring hereditary dysfibrinogenemia.
METHODSProthrombin time(PT), activated partial thromboplastin time(APTT), thrombin time(TT), calibration of plasma protamine sulfate against TT, fibrinogen (Fg) activity, coagulation factors II, V, VII, VIII, IX, X, XI and XII of all probands and their family members were detected with an automatic blood coagulation analyzer; D-dimer(D-D) and fibrin(ogen) degradation products(FDPs) were also dtected by automatic blood coagulation analyzer, Fg antigen were detected with an immunoturbidimetry method. Exons of fibrinogen genes FGA, FGB and FGG and flanking sequences were amplified by polymerase chain reaction(PCR) and sequenced.
RESULTSAll of the probands showed normal levels of FDPs, D-dimer(D-D) and activity of coagulation factor II,V,VII, VIII, IX,X,XI, XII. Plasma PT and APTT were normal or slightly prolonged. Prolonged TT was found in all of the probands, whilst TT was not significantly shortened by protamine sulfate. Fg antigen was within the normal range, but Fg activity was significantly decreased. The Fg antigen/activity ratio was greater than 2. One proband has carried a heterozygous variant of the FGA gene g.1233G>A(p.A α Arg35His). Four have carried a heterozygous mutation of the FGB gene g.9692A>G(p.Bβ Asn190Ser). The remaining 3 had heterozygous substitution of FGG gene g.10819G>A(p.γ Arg301His). In addition, 2 polymorphisms (p.A α Thr331Ala) and p.B β Arg478Lys) were identified in FGA and FGB genes.
CONCLUSIONp.A α Arg35His, p.B β Asn190Ser and p. γ Arg301His are responsible for the inherited dysfibrinogenemia in the 8 Chinese pedigrees. p.B β Asn190Ser is firstly reported in China. p.B β Asn190Ser and p. γ Arg301His may be mutation hot spot in the Chinese population.
Afibrinogenemia ; blood ; genetics ; Fibrin Fibrinogen Degradation Products ; analysis ; Fibrinogen ; analysis ; genetics ; Humans ; Pedigree
7.Congenital afibrinogenemia caused by a novel insertion mutation in the FGB gene.
Jian ZHANG ; Xiao-juan ZHAO ; Zhao-yue WANG ; Zi-qiang YU ; Li-Juan CAO ; Zhen-ni MA ; Jie ZHANG ; Wei ZHANG ; Xia BAI ; Chang-geng RUAN
Chinese Journal of Hematology 2013;34(9):751-756
OBJECTIVETo investigate the genetic defect and its mechanism in a patient with congenital afibrinogenemia.
METHODSThe plasma fibrinogen activity and antigen of the patient was determined using the Clauss method and immuno-nephelometric assay, respectively. Genomic DNA was isolated from peripheral blood of the proband and his related family members. All exons and exon-intron boundaries of the three fibrinogen genes (FGA, FGB, FGG) were amplified by PCR followed by direct sequencing. Thrombin fibrin aggregation curve were detected in the plasma of the patient. Wild-type and mutation type fibrinogen vectors were constructed, and then transfected into COS-7 cells. The wild-type and mutant proteins from the culture media and cell lysates were tested by Western blot and ELISA.
RESULTSAPTT, PT, TT were significantly longer in the proband. Plasma fibrinogen activity and antigen of the patient could not be detected using the Clauss method and immuno-nephelometry, respectively. Gene analysis revealed that a novel homozygous GTTT insertion between nucleotides 2833 and 2834 in FGB exon 2 in the proband. The proband's father, mother, brother and son were heterozygous. The polymerization curves of the patient did not show a lag phase or final turbidity, compared with the normal controls. Western blot analysis showed the lack of complete half-molecules of the fibrinogen molecule and fibrinogen in patient's plasma under non-reducing conditions. It also could not detect the truncated Bβ chain under reducing conditions. Abnormal fibrinogen molecule (molecule weight>340 000) were found in transfected COS-7 cells by Western blot, which indicated that the mutation caused the abnormal intracellular fibrinogen molecule assembly. The fibrinogen band was absent in culture media transfected by the mutation. Fibrinogen levels of mutant fibrinogen were no significant different from those of wild-type fibrinogen in cell lysates by ELISA analysis [(2.47 ± 0.30) μg/ml vs (2.65±0.60) μg/ml, P=0.0889]; However, the levels of the mutant fibrinogen were statistically significant lower than those of wild type fibrinogen in culture media [(0.01 ± 0.01) μg/ml vs (3.80±0.80) μg/ml, P=0.0001].
CONCLUSIONCongenital afibrinogenemia was caused by this frameshift mutation in exon 2 of FGB. This novel mutation impaired fibrinogen assembly and secretion.
Afibrinogenemia ; congenital ; etiology ; genetics ; Fibrinogen ; genetics ; Frameshift Mutation ; Humans ; Male ; Mutagenesis, Insertional ; Pedigree ; Young Adult
9.Analysis of a pedigree affected with congenital hypofibrinogenemia due to heterozygous Ser313Ile mutation of fibrinogen γ chain gene.
Liqing ZHU ; Misheng ZHAO ; Xiaoli CHENG ; Dandan YU ; Xiaolong LI ; Fei XU ; Jinguo WANG ; Mingshan WANG
Chinese Journal of Medical Genetics 2018;35(2):179-183
OBJECTIVETo explore the genetic basis for a Chinese pedigree affected with congenital hypofibrinogenamia.
METHODSPeripheral blood samples were collected from 9 members from the pedigree. Routine coagulation tests including activated partial thromboplastin time (APTT), thrombin time (TT), the prothrombin time (PT) were carried out. The activity of fibrinogen (Fg: C) was measured using Clauss method, and fibrinogen antigen (Fg: Ag) was measured with immunoturbidimetry. All exons and exon-intron boundaries of the fibrinogen Aα, Bβ and γ chain genes were amplified using PCR, which was followed by direct sequencing. Suspected mutation was confirmed by reverse sequencing. The mutant fibrinogen was analyzed with Swiss-PdbViewer.
RESULTSThe proband showed prolonged APTT, PT and TT. Her functional fibrinogen (Fg: C) and antigen fibrinogen (Fg: Ag) levels were reduced to 0.69 g/L and 0.72 g/L, respectively. Her mother and grandmother also had a low levels of fibrinogen, which were 0.99 g/L and 0.83 g/L for Fg: C, 1.02 g/L and 0.87 g/L for Fg: Ag, respectively. The results of other members from the pedigree were all within the normal range. Genetic analysis reveled a heterozygous G>T mutation at nucleotide 7590 in exon 8 of γ gene in the proband, which was predicted to be a novel Ser313Ile mutation. The mutation was also found in her mother and grandmother. Model analysis showed that the Ser313Ile mutation disturbed the hydrogen bonds between Ser313, Asn319 and Asp320. Moreover, the mutation also altered the mutual electrostatic force and affected the folding and instability of the mutant fibrinogen.
CONCLUSIONThe heterozygous Ser313Ile mutation probably underlies the hypofibrinogenemia in this pedigree.
Adult ; Afibrinogenemia ; genetics ; Female ; Fibrinogen ; chemistry ; genetics ; Heterozygote ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree
10.Genetic analysis of an inherited afibrinogenemia family caused by a novel frameshift mutation in FGA.
Feng XUE ; Jing GE ; Dong-Sheng GU ; Wei-Ting DU ; Tao SUI ; Hai-Feng ZHAO ; Lei ZHANG ; Ren-Chi YANG
Journal of Experimental Hematology 2009;17(4):1021-1025
Inherited afibrinogenemia is a rare autosomal recessive bleeding disease characterized by complete absence of fibrinogen in blood. To identify the genotype in a Chinese family with inherited afibrinogenemia, the samples of peripheral blood were collected from 6 members of 3 generations. The activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and fibrinogen (Fg, clauss) were tested. Fg was also analyzed by using immunoturbidimetry method. DNAs of six members were extracted by using a DNA extract kit. All the exons and exon-intron boundaries of the three fibrinogen genes were amplified by using PCR and analyzed by direct sequencing. The results showed that the parents of proband were 3 degree consanguinity. A homozygous c.934_935insA in FGA was found in proband which results in the change of protein p.Ser312fsX42. The parents, grandmother, maternal grandmother and father's sister were all detected with heterozygous mutation which was same as that in proband. In conclusion homozygous c.934_935insA in FGA is a cause of inherited afibrinogenemia and a novel mutation being reported.
Afibrinogenemia
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etiology
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genetics
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Child
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Exons
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Female
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Fibrinogen
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genetics
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Frameshift Mutation
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Heterozygote
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Humans
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Male
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Pedigree