Two symptomatic cases of dysfibrinogenemia in China: one with gamma-chain Arg275Cys mutation and another without detectable mutation in fibrinogen genes.

The aim of this study was to investigate causative mutations of two unrelated symptomatic Chinese children with dysfibrinogenemia and their family members.Fibrinogen genes, including FGA, FGB and FGG of all participants were PCR-amplified, followed by direct sequencing. Precipitated plasma fibrinogen of some family members was analyzed by western blotting, fibrin polymerization and scanning electron microscopy (SEM).Proband 1 associated with frequent epistaxis was identified to harbor a heterozygous Arg275Cys mutation in FGG, along with a polymorphism Arg448Lys in FGB. Proband 2 with apparently prolonged thrombin time and very low functional fibrinogen had undergone both spontaneous intracranial hemorrhages and deep venous thrombosis. Sequencing of all proximal promoters, coding regions, introns and 3'-untranslated region using genomic DNA of Proband 2 yielded no mutation in three fibrinogen genes. Western blotting of this patient's precipitated plasma fibrinogen detected no truncated protein. Fibrinogen polymerization curve showed prolonged lag phase and severely decreased final turbidity, and SEM observations of fibrin clots made from Proband 2 revealed an abnormal sponge-like mass with large pores. We speculate that other underlying mechanisms responsible for dysfibrinogenemia such as abnormal posttranscriptional processing or posttranslational modification, which are independent of detectable mutations in the genomic DNA sequence, may exist.