Fibrinogen Hershey IV: a novel dysfibrinogen with a gammaV411I mutation in the integrin alpha(IIb)beta(3) binding site. Thromb Haemost 2008 Jun;99(6):1008-12
Date
06/04/2008Pubmed ID
18521501Pubmed Central ID
PMC4089099DOI
10.1160/TH07-06-0427Scopus ID
2-s2.0-44949196653 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
The carboxyl terminal segment of the fibrinogen gamma chain from gamma408-411 plays a crucial role in platelet aggregation via interactions with the platelet receptor alpha(IIb)beta(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, gammaV411I and gammaR275C. 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 V411I mutation as compared to the wild-type dodecapeptide. Purified fibrinogen Hershey IV also bound to purified platelet alpha(IIb)beta(3) with a lower affinity than wild-type fibrinogen. These findings show that the gammaV411I 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.
Author List
Flood VH, Al-Mondhiry HA, Rein CM, Alexander KS, Lovely RS, Shackleton KM, David LL, Farrell DHAuthor
Veronica H. Flood MD Chief, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Binding SitesBlood Platelets
DNA Mutational Analysis
Female
Fibrinogens, Abnormal
Heterozygote
Humans
Middle Aged
Platelet Aggregation
Platelet Glycoprotein GPIIb-IIIa Complex
Point Mutation
Protein Binding
