Analysis of phenotype and genotype in two Chinese pedigrees with inherited hypofibrinogenemia caused by γTrp208Leu
1.Department of Clinical Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015; 2.Department of Clinical Laboratory, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027
YANG Lihong1,HAO Xiuping1,DING Hongxiang2, et al. Analysis of phenotype and genotype in two Chinese pedigrees with inherited hypofibrinogenemia caused by γTrp208Leu[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2015, 45(7): 525-.
Abstract：Objective: To analyze the phenotype and genotype of two Chinese pedigrees with inherited hypofibrinogenemiaidentify by the same mutation. Methods: Laboratory tests, including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), plasminogen activity (PLG:C), and fibrinogen degradation products (FDPs) were detected in two pedigrees. The activity and antigen plasma fibrinogen (Fg:C, Fg:Ag) were analyzed by Clauss and immunoturbidimetry methods respectively. All the exons and exon-intron boundaries of the three Fg genes FGA, FGB and FGC were amplified by PCR and followed by direct sequencing. The mutation was analyzed by the Swiss-Model and PIC. Results: Two probands had normal PT, APTT, PLG:A and FDPs, but slightly prolonged TT. The Fg:C of the two probands were significantly reduced, 0.49 g/L and 0.63 g/L respectively. Their Fg:Ag were both significantly reduced, 0.63 g/L and 0.77 g/L respectively. These abnormalities were also found in his grandma and father of proband A, mother, aunt and cousin of proband B. Genetic analysis revealed a heterozygous G>T change at nucleotide 5792 in exon 7 of FGG gene in the two probands, predicting a heterozygous Trp208Leu mutation. Model analysis showed that the Trp208Leu mutation is disrupted the native hydrogen bonding network of Thr314, and changed the molecular geometries, increasing instability of the protein. Conclusion: Inherited hypofibrinogenemia in those two pedigrees were caused by heterozygous Trp208Leu mutation in the γ chain of Fg.
[1] Mosesson MW. Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation[J]. Thromb Haemost, 2003, 89(1): 9-12.
[2] Frenkel E, Duksin C, Herman A, et al. Congenital hypofibrinogenemia in pregnancy: report of two cases and review of the literature[J]. Obstet Gynecol Surv, 2004, 59(11): 775-779.
[3] Moerloose P, Boehlen F, Neerman-Arbez M. Fibrinogen and the risk of thrombosis[J]. Semin Thromb Hemost, 2010, 36(1): 7-17.
[4] KoeninW. Fibrinogen in cardiovascular disease update[J]. Thromb Heamost, 2003, 89(4): 601-609.
[5] 姜林林, 王学锋, 丁秋兰, 等. 四例遗传性异常纤维蛋白原血症患者基因型和凝血功能分析[J]. 中华血液学杂志,2012, 33(6): 475-479.
[6] Fujihara N, Haneishi A, Yamauchi K, et al. A C-terminal amino acid substitution in the γ-chain caused by a novel heterozygous frameshift mutation (Fibrinogen Matsumoto VII) results in hypofibrinogenaemia[J]. Thromb Haemost, 2010, 104(2): 213-223.
[7] Peyvandi F, Haertel S, Knaub S, et a1. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia[J]. Thromb Haemost, 2006, 4(7): 1634-1637.
[8] 江明华, 王晓欧, 舒旷怡, 等. 八个遗传性异常纤维蛋白原血症家系的临床和基因突变分析[J]. 中华医学遗传学杂志, 2014, 31(2): 134-139.
[9] Brennan SO, Davis RL, Conard K, et al. Novel fibrinogen mutation γ314Thr→Pro (fibrinogen AI duPont) associated with hepatic fibrinogen storage disease and hypofibrinogenae-mia[J]. Liver International, 2010, 30(10): 1541-1547.
