The β-chain mutation p.Trp433Stop impairs fibrinogen secretion: A novel nonsense mutation associated with hypofibrinogenemia

Background: Congenital hypofibrinogenemia is characterized by proportional decreases in fibrinogen activity and immunoreactive fibrinogen levels. Here, we describe a new case with the bleeding risk identified in our hospital.

Methods: The proband was cut and bled for 3 h. Coagulation testing, gene analysis, thrombelastogram, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), in vitro plasmid construction, and functional analyses were performed to explore the pathogenic mechanism.

Results: Coagulation testing of the male proband revealed low levels of fibrinogen detected by two methods (the Clauss method and the PT-derived method); his two sons had normal coagulation results. DNA sequencing of the proband revealed a heterozygous point mutation in exon 8 of the FGB gene causing Trp→Stop substitution and a polymorphic site (p.Leu92Phe). Human Trp433 was found to be highly conserved. SDS-PAGE showed that the fibrinogen level of the proband was markedly lower than that of healthy controls. Using high-performance liquid chromatography-mass spectrometry, a mutated Bβ chain was not detected in circulation. In vitro expression analyses indicated that the mutation affected the secretion of fibrinogen. The TEG results indicated that the proband had a prolonged K time, a lower CI value, and a lower angle value.

Conclusion: We report a new case with a novel nonsense mutation that resulted in hypofibrinogenemia. The results indicate that the nonsense mutation may cause misfolding of the D domain, which then affects the secretion of fibrinogen.