一种新型纤维蛋白原β链错义突变导致的遗传性低纤维蛋白原血症

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Abstract Objective: To identify the genetic defect underlying congenital hypofibrinogenamia in a Chinese pedigree. Methods: Totally 6 family members were enrolled in this study. Routine coagulation tests, including activated partial thromboplastin time (APTT), thrombin time (TT), the prothrombin time (PT), D-Dimer (DD) and fibrinogen degradation products (FDPs) were determined. The activity of fibrinogen (Fg:C) was measured using Clauss method and fibrinogen antigen (Fg:Ag) was measured using immunoturbidimetry. All exons and exon-intron boundaries of the fibrinogen Aα, Bβ and γ chain gene were amplified using PCR, followed by direct sequencing. Suspected mutation was further confirmed by reverse sequencing. The mutant fibrinogen was analyzed by the Swiss-PdbViewer, ClustalX-2.1-win and other online software. Results: PT and TT were prolonged in the proband. Her functional fibrinogen (Fg:C) and antigen fibrinogen (Fg:Ag) levels were reduced, which was 0.82 g/L and 1.19 g/L, respectively. Genetic analysis revealed a heterozygous T>G change at nucleotide 425 in exon 3 of FGB gene in the proband, predicting a novel Leu121Arg mutation. This mutation was also found in her father and son. Model analysis showed that the Leu121Arg mutation added a hydrogen bonding among Try117, Met118, Trp125 and Leu121. Moreover, the mutation also changed the mutual electrostatic forces, affecting the folding and instability of the mutant fibrinogen. Conclusion: The heterozygous Leu121Arg mutation leading to the hypofibrinogenemia in this pedigree.

Key words： congenital hypofibrinogenemia pedigree gene mutation model analysis

Received: 15 February 2019

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	ZHU Liqing
	ZHANG Haiyue
	LUO Shasha
	FANG Weiwei
	LIU Siqi
	SU Kankan
	YANG Lihong
	WANG Mingshan.

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https://xb.wmu.edu.cn/EN/ OR https://xb.wmu.edu.cn/EN/Y2019/V49/I5/339

[1] 邹杨, 刘园, 黄薇, 等. STAT3抗肿瘤抑制剂的研究进展[J]. 药学学报, 2018, 53(10): 1598-1608.
[2] 张大永, 吴家强, 吴晓明. STAT3抑制剂及其抗肿瘤活性研究进展[J]. 药学进展, 2012, 36(7): 289-299.
[3] BROMBERG J, DARNELL J E. The role of STATs in transcriptional control and their impact on cellular function[J]. Oncogene, 2000, 19(21): 2468-2473.
[4] 高安定, 林宝顺, 兰小鹏. STAT3与肿瘤[J]. 中国生物化学与分子生物学报, 2013, 29(5): 397-403.
[5] CHAI E Z P, SHANMUGAM M K, ARFUSO F, et al. Targeting transcription factor STAT3 for cancer prevention and therapy[J]. Pharmacol Ther , 2016, 162: 86-97.
[6] FURTEK S L, BACKOS D S, MATHESON C J, et al. Strategies and approaches of targeting STAT3 for cancer treat-ment[J]. ACS Chem Biol , 2016, 11(2): 308-318.
[7] 祝立和, 胡卢丰, 季剑乐, 等. 抑制STAT3活化对GD2阳性乳腺癌干细胞自我更新能力的影响[J]. 温州医科大学学报, 2018, 48(2): 110-114.
[8] 李庆伟, 褚丹, 王继红. STAT3信号转导通路及肿瘤治疗的方法[J]. 沈阳师范大学学报(自然科学版), 2009, 27(2): 230-235.
[9] HE M, YANG Z Y, ZHANG L, et al. Additive effects of cherlerythrine chloride combination with erlotinib in human non-small cell lung cancer cells[J]. PLoS One, 2017, 12(4): e0175466.
[10] WANG G, ZHANG B, WANG Y, et al. Crocin promotes apoptosis of human skin cancer cells by inhibiting the JAK/STAT pathway[J]. Exp Ther Med , 2018, 16(6): 5079-5084.
[11] CHEN D, ZHANG F, WANG J, et al. Biodegradable nanoparticles mediated co-delivery of erlotinib (ELTN) and fedratinib (FDTN) toward the treatment of ELTN-Resistant non-small cell lung cancer (NSCLC) via suppression of the JAK2/STAT3 signaling pathway[J]. Front Pharmacol, 2018, 9: 1214.
[12] XIONG A L, YANG Z D, SHEN Y C, et al. Transcription factor STAT3 as a novel molecular target for cancer preven-tion[J]. Cancers, 2014, 6(2): 926-957.
[13] YANG X O, PANOPOULOS A D, NURIEVA R, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells[J]. J Biol Chem, 2007, 282(13): 9358-9363.
[14] YANG X, LIN Y, SHI Y, et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling[J]. Cancer Res, 2016, 76(14): 4124-4135.
[15] NIE Y, LI Y, HU S. A novel small inhibitor, LLL12, targets STAT3 in non-small cell lung cancer in vitro and in vivo[J]. Oncol Lett, 2018, 16(4): 5349-5354.
[16] XIAO H, BID H K, JOU D, et al. A novel small molecular STAT3 inhibitor, LY5, inhibits cell viability, cell migration, and angiogenesis in medulloblastoma cells[J]. J Biol Chem, 2015, 290(6): 3418-3429.
[17] SHAHANI V M, YUE P, HAFTCHENARY S, et al. Identification of purine-scaffold small-molecule inhibitors of Stat3 activation by QSAR studies[J]. ACS Med Chem Lett, 2011, 2(1): 79-84.
[18] MASCIOCCHI D, GELAIN A, VILLA S, et al. Signal transducer and activator of transcription 3 (STAT3): a promising target for anticancer therapy[J]. Future Med Chem, 2011, 3(5): 567-597.
[19] ZHANG Y, LV H D, LUO L, et al. Design, synthesis and pharmacological evaluation of N4, N6-disubstituted pyrimidine-4, 6-diamine derivatives as potent EGFR inhibitors in non-small cell lung cancer[J]. Eur J Med Chem, 2018, 157: 1300-1325.
[20] WANG X B, HAN C, WU K Q, et al. Design, synthesis and ability of non-gold complexed substituted purine derivatives to inhibit LPS-induced inflammatory response[J]. Eur J Med Chem, 2018, 149: 10-21.
[21] 王博, 张英, 王林玉, 等. STAT3荧光素酶报告基因检测系统的构建及其检测STAT3活化能力的研究[J]. 山西医科大学学报, 2017, 48(11): 1108-1113.
[22] 罗奇志, 林琳, 王芙艳, 等. MTT方法的优化[J]. 激光生物学报, 2014, 23(3): 279-282.
[23] CHEN H, PAN J, ZHANG L, et al. Downregulation of estrogen-related receptor alpha inhibits human cutaneous squamous cell carcinoma cell proliferation and migration by regulating EMT via fibronectin and STAT3 signaling pathways [J]. Eur J Pharmacol, 2018, 825: 133-142.
[24] JI L, LIU X, ZHANG S, et al. The novel triazolonaphthalimide derivative LSS-11 synergizes the anti-proliferative effect of paclitaxel via STAT3-dependent MDR1 and MRP1 downregulation in chemoresistant lung cancer cells[J]. Molecules, 2017, 22(11). pii: E1822.
[25] CARPENTER R L, LO H W. STAT3 target genes relevant to human cancers[J]. Cancers (Basel), 2014, 6(2): 897-925.
[26] ABDELHAMED S, OGURA K, YOKOYAMA S, et al. AKT-STAT3 pathway as a downstream target of EGFR signaling to regulate PD-L1 expression on NSCLC cells[J]. J Cancer, 2016, 7(12): 1579-1586.
[27] 韩春生, 陈艳, 伍学强. STAT3在肿瘤形成中的作用[J]. 中国实验血液学杂志, 2013, 21(2): 517-520.