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標題: 一個因纖維蛋白原阿爾法鏈基因點突變造成異常纖維蛋白原血症之台灣家族的研究
The study of a Taiwanese family with dysfibrinogenemia due to a genetic point mutation in fibrinogen alpha chains
作者: 蕭玉鑫
Hsiao, Yu-Hsin
關鍵字: fibrinogen;纖維蛋白原;dysfibrinogenemia;異常纖維蛋白原血症
出版社: 生命科學院碩士在職專班
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Grieninger 2000. The aEC domain of human fibrinogen-420 is a stable and early plasmin cleavage product. Blood 95: 2297-2303. Asselta, R., S. Duga, S. Spena, F. Peyvandi, G. Castaman, M. Maicovati, P. Mannucci, and M. L. Tenchini 2004. Missense or splicing mutation? The case of a fibrinogen Bb-chain mutation causing severe hypofibrinogenemia. Blood 103: 3051-3054. Asselta, R., S. Duga, E. Santagostino, F. Peyvandi, G. Piseddu, R. Targhetta, M. Malcovati, P. Mannucci, and M. Luisa Tenchini 2001. Congenital afibrinogenemia: mutations leading to premature termination codons in fibrinogen Aa-chain gene are not associated with the decay of the mutant mRNAs. Blood 96: 3685-3692. Attanasio, C., A. David, and M. Neeman-Arbez 2003. Outcome of donor splice site mutations accounting for congenital afibrinogenemia reflects order of intron removal in the fibrinogen alpha gene (FGA). Blood 101: 1851-1856. Bolliger-Stucki, B., S. T. Lord, and M. Furian 2001. 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Germanos-Haddad, K. Tzanidakis, D. Vu, S. Deutsch, A. David, M. A. Morris, and P. de Moerloose 2004. Expression and analysis of a split premature termination codon in FGG responsible for congenital afibrinogenemia: escape form RNA surveillance mechanisms in transfected cells. Blood 104: 3618-3623. Ni, F., Y. C. Meinwald, M. Vasquez, and H. A Scheraga 1989 High-Resolution NMR Studies of fibrinogen-like peptides in solution: structure of a thrombin-bound peptide corresponding to residues 7-16 of the Aa chain of human fibrinohen. Biochemistry 28: 3094-3105.(Abstrate) Qiu, L. L., Stanley S. L., Kristen L. K., and R. J. Elin 2003. Convenient and effective method for gemoving fibrinogen from serum specimens before protein elctrophoresis. Clinical Chemistry 49: 868-872. Southan, C., D.A. Lane, W Bode, and A. Henschen 1985. Thrombin-inciduced fibrinopeptode release from a fibrinogen variant (Fibrinogen Sydney I) with an Aalpha Arg-16----His substitution. 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本論文是對一具功能異常的纖維蛋白原 (fibrinogen)變異型之台灣家族所做的研究,其fibrinogen genes具有一核酸 (nucleotide)取代之異合子 (heterozygous)點突變 (point mutation)導致coden由CTA變成CCA,使fibrinogen Aa鏈之FGA gene第9個氨基酸 (amino acid) leucine被proline所取代。此種纖維蛋白原變異型 (fibrinogen variant)是屬 「fibrinogen Magdeburg I」,此variant早在1987年已於一德國家族中被發現,而在2003年完成DNA分析,同時也顯示於FGA基因第1182個核苷酸(exon 2)發生T變C之點突變,而使原來第9個amino acid的leucine被proline所代替。而我們所研究的台灣這一個異常纖維蛋白血症(dysfibrinogenemia)家族,首先發現於一位患有B型肝炎的53歲男性,發現其有中度延長凝血酶原時間 (prothrombin time),但活化部分凝血活酶時間 (activated partial thromboplastin time)是正常。於之前外科手術時並無紀錄有出血傾向或有關出血併發症,再進一步做凝血相關檢查,凝血酶時間 (thrombin time)之結果顯示延長,檢測fibrinogen活性之結果呈現hypofibrinogen (70.4 mg/dL),但檢測血漿中fibrinogen之抗原量顯示不一致的結果。於此家族研究發現三代家族9個成員中有6個人皆顯示hypofibrinogen活性之結果,因此我們執行fibrinogen之FGA、FGB及FGG三個基因之分析,將三個基因之所有exons及exon-intron連結處之基因先分別進行聚合連鎖反應(PCR),再以直接定序方式利用自動化核酸定序儀進行序列分析。我們的研究結果亦顯示於FGA基因第1182位置呈現核苷酸(CàT)異合子錯誤突變而造成第9個氨基酸leucine與proline交換,此amino acid exchange造成fibrinogen N-terminal構型改變,使得於fibrinogen形成fibrin時,凝血酶 (thrombin)會於fibrinogen Aa chains N-terminal之第16 amino acid與第17 amino acid間 (Aa chain 16, Arg-17 Gly bond)和Bb chains N-terminal之第15 amino acid與第16 amino acid (Aa chain 15, Arg-16 Gly bond)間切割,產生各2個片段之fibrinopeptide A及fibrinopeptide B,但因突變造成fibrinogen N-terminal構型改變使得fibrinopeptide A釋放的速率延長,fibrin的形成亦同時延長。

We report a dysfunctional fibrinogen variant, which has a heterozygous point mutation from CTA to CCA leading to AaLeu9Pro in a Taiwanese family. This fibrinogen variant was compatible with fibrinogen Magdeburg I as first discovered in a Germany family in 1987. The mutation was verified in 2003 to be a heterozygous T-to-C point mutation at position 1182 of the FGA gene (exon 2) which substituted a proline for a leucine at position 9. In the present study of a Taiwanese family of hypofibrinogenemia, a 53-year-old male with chronic HBV hepatitis was found to have a mild prolonged prothrombin time (PT) but normal activated partial thromboplastin time (aPTT). No bleeding tendency or hemorrhagic complication during operation was noted previously. Further coagulation work up was carried out at prolonged thrombin time (TT) and measurement of fibrinogen activity revealed severe hypofibrinogenemia (70.4 mg/dL) in the proband. However, plasma antigenic level of fibrinogen measurement was shown to be normal. The family study showed a similar dysfibrinogenemia in six other family members representing three generations of this family. All exons and exon-intron boundaries in three fibrinogen genes for FGA, FGB and FGG chains were respectively amplified using polymerase chain reaction (PCR) and direct sequencing of PCR products were performed on an automated nucleic acid sequencer. The genetic study reveals heterozygous for a missense mutation T1182C in the FGA gene causing the amino acid exchange from leucine to proline at position 9. This mutant fibrinogen results in a conformational change of a-helical stretch unfavorable for thrombin cleavage on fibrinogen (Aa chain 16, Arg-17 Gly bond) and causes delayed release of abnormal fibrinopeptide A in forming fibrin.
其他識別: U0005-3001200822091900
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