Fibrinogen Hershey IV: A novel dysfibrinogen with a γV4 I I I mutation in the integrin αIIbβ3 binding site

The carboxyl terminal segment of the fibrinogen y chain from γ408-4II plays a crucial role in platelet aggregation via interactions with the platelet receptor α IIb β 3 .We describe here the first naturally-occurring fibrinogen point mutation affecting this region and demonstrate its effects on platelet interactions. DNA sequencing was used to sequence the proband DNA, and platelet aggregation and direct binding assays were used to quantitate the biological effects of fibrinogen Hershey IV. The Hershey IV proband was found to be heterozygous for two mutations, γV4III and γR275C. Little difference in aggregation was seen when fibrinogen Hershey IV was compared to normal fibrinogen. However, less aggregation inhibition was observed using a competing synthetic dodecapeptide containing the V4III mutation as compared to the wild-type dodecapeptide. Purified fibrinogen Hershey IV also bound to purified platelet α IIb β 3 with a lower affinity than wild-type fibrinogen.These findings show that the γV4III mutation results in a decreased ability to bind platelets. In the heterozygous state, however, the available wild-type fibrinogen appears to be sufficient to support normal platelet aggregation.