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

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.