Phenotypic and glycosylation profiles of the FGG c.902G > A (p.Arg301His) mutation in a Chinese pedigree with congenital dysfibrinogenemia

IF 3.4 3区医学 Q1 HEMATOLOGY

Thrombosis research Pub Date : 2026-08-01 DOI:10.1016/j.thromres.2026.109793

Xiaozhen Kang, Luoyuan Cao, Weitong Peng, Xianxiang Peng, Jiaojiao Lu, Tao Zhang, Shouzhong Wei

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引用次数: 0

Abstract

Objective

Congenital dysfibrinogenemia (CD) is characterized by functionally impaired fibrinogen. This study aimed to characterize the phenotypic, molecular, and clinical features associated with the FGG p.Arg301His mutation in a Chinese pedigree.

Methods

A Chinese pedigree comprising 12 members was enrolled, including 6 individuals carrying the FGG p.Arg301His mutation. Phenotypic evaluation was performed using conventional coagulation tests, thromboelastography (TEG), and thrombosis biomarker panels. Fibrinogen was purified from plasma and subjected to structural analysis via SDS-PAGE and LC-MS/MS mass spectrometry. Glycosylation profiles of the fibrinogen γ-chain were compared between mutation carriers and healthy controls. Molecular modeling was conducted to predict the structural effects of the mutation.

Results

Conventional coagulation tests combined with TEG effectively identified a hypocoagulable state in mutation carriers, whereas thrombosis biomarker panels showed limited diagnostic value. Structural analysis revealed markedly increased O-glycosylation sites (17 vs. 3) and N-glycosylated peptides (5 vs. 3) in the fibrinogen γ-chain of mutation carriers compared with controls. A unique glycan HexNAc(6)Hex(4)Fuc(2) was detected exclusively in the mutation group. Bioinformatic modeling predicted that the p.Arg301His substitution reduces hydrogen bonding, leading to conformational destabilization (ΔΔG ranging from −0.08 to −1.211 kcal/mol.). Clinically, female carriers experienced miscarriage and postpartum hemorrhage, while male carriers remained asymptomatic.

Conclusion

The FGG p.Arg301His mutation induces aberrant glycosylation and structural alterations in fibrinogen, contributing to functional impairment and a hypocoagulable state. These molecular changes may underlie the obstetric complications observed in female carriers. Integration of genetic, functional, glycosylation, and conformational analyses is of great significance for accurate assessment of bleeding and obstetric complication risks in patients with CD.

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中国先天性异常纤维蛋白原血症家系FGG c.902G > A （p.a g301his）突变的表型和糖基化谱

目的：先天性纤维蛋白异常血症（CD）以纤维蛋白原功能受损为特征。本研究旨在描述一个中国家系FGG p.a g301his突变的表型、分子和临床特征。方法：选取12个中国家系，其中6个携带FGG p.a g301his突变。表型评估采用常规凝血试验、血栓弹性成像（TEG）和血栓生物标志物面板。从血浆中纯化纤维蛋白原，并通过SDS-PAGE和LC-MS/MS质谱进行结构分析。比较突变携带者与健康对照间纤维蛋白原γ链的糖基化谱。分子模型被用来预测突变的结构效应。结果：常规凝血试验联合TEG可有效识别突变携带者的低凝状态，而血栓生物标志物面板的诊断价值有限。结构分析显示，与对照组相比，突变携带者纤维蛋白原γ-链上的o -糖基化位点（17个）和n -糖基化肽（5个）明显增加。在突变组中只检测到独特的聚糖HexNAc(6)Hex(4)Fuc(2)。生物信息学模型预测p.a g301his取代降低了氢键，导致构象不稳定（ΔΔG范围从-0.08到-1.211 kcal/mol.）。临床上，女性携带者出现流产和产后出血，而男性携带者无症状。结论：FGG p.a g301his突变引起纤维蛋白原异常糖基化和结构改变，导致功能损伤和低凝状态。这些分子变化可能是在女性携带者中观察到的产科并发症的基础。整合遗传、功能、糖基化和构象分析对准确评估CD患者出血和产科并发症风险具有重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Thrombosis research 医学-外周血管病

CiteScore

14.60

自引率

4.00%

发文量

364

审稿时长

31 days

期刊介绍： Thrombosis Research is an international journal dedicated to the swift dissemination of new information on thrombosis, hemostasis, and vascular biology, aimed at advancing both science and clinical care. The journal publishes peer-reviewed original research, reviews, editorials, opinions, and critiques, covering both basic and clinical studies. Priority is given to research that promises novel approaches in the diagnosis, therapy, prognosis, and prevention of thrombotic and hemorrhagic diseases.