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An arginine to cysteine amino acid substitution at a critical thrombin
cleavage site in a dysfunctional factor VIII molecule
M Shima, J Ware, A Yoshioka, H Fukui and CA Fulcher
Scripps Clinic and Research Foundation, La Jolla, CA.
We have analyzed the factor VIII (FVIII) protein and the nucleotide
sequence around two thrombin cleavage sites, at arginine 372 in the FVIII
heavy chain and arginine 1689 in the FVIII light chain in a naturally
occurring dysfunctional FVIII variant, FVIII Okayama. The patient was a
42-year-old hemophiliac with a FVIII coagulant activity of 0.03 U/mL and a
FVIII antigen level of 0.8 U/mL. The patient's FVIII was not thrombin
activatable to levels seen in normal plasma. Immunoblotting of partially
purified FVIII Okayama and normal FVIII showed that thrombin cleavage of
the 92 kilodalton (Kd) heavy chain was impaired in the mutant protein. The
patient's genomic DNA was amplified using the polymerase chain reaction
with two sets of synthetic oligonucleotide primers spanning amino acid
residues 319 to 400 and 1630 to 1720. Sequence analysis of the amplified
DNA fragments revealed a cytosine to thymine transition, converting an
arginine to a cysteine codon at residue 372. No abnormality was found in
the FVIII light chain region analyzed. The patient's hemophilic brother and
carrier mother revealed the same mutation. We conclude that the
pathogenesis of hemophilia A in this patient is probably due to an arginine
to cysteine substitution at a thrombin cleavage site in the FVIII heavy
chain.
Volume 74,
Issue 5,
pp. 1612-1617,
10/01/1989
Copyright © 1989 by The American Society of Hematology
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