Characterization of a thrombin cleavage site mutation (Arg 1689 to Cys) in
the factor VIII gene of two unrelated patients with cross-reacting
material-positive hemophilia A
M Arai, M Higuchi, SE Antonarakis, HH Kazazian , JA Phillips , RL Janco and LW Hoyer
Jerome H. Holland Laboratory for the Biomedical Sciences, American Red
Cross Blood Services, Rockville, MD.
The molecular defect responsible for moderate and severe hemophilia A has
been identified for two unrelated patients with the CRM-positive form of
this disorder (factor VIII activity of 0.02 and 0.05 U/mL with factor VIII
antigen of 0.87 and 2.20 U/mL). In both cases, the immunopurified
dysfunctional factor VIII protein is abnormal, in that the 80 Kd light
chain is not cleaved by thrombin at arginine-1689. The basis for this
failure was identified by polymerase chain reaction amplification of exon
14 of the variant factor VIII genes and direct sequencing of the amplified
products. In both cases, a single base substitution (C to T) was identified
that produces an arginine to cysteine substitution at amino acid residue
1689. These data identify the molecular defects of the two identical factor
VIII variant proteins. The dysfunctional factor VIII has been designated
"Factor VIII-East Hartford," the residence of the patient in whom the
defect was first identified.
Volume 75,
Issue 2,
pp. 384-389,
01/15/1990
Copyright © 1990 by The American Society of Hematology
