Molecular basis of a hereditary type I protein S deficiency caused by a
substitution of Cys for Arg474
T Yamazaki, A Katsumi, K Kagami, Y Okamoto, I Sugiura, M Hamaguchi, T Kojima, J Takamatsu and H Saito
First Department of Internal Medicine, Nagoya University School of
Medicine, Nagoya, Japan.
The molecular basis for a hereditary type I protein S (PS) deficiency was
investigated. DNA sequence analysis in the proband showed a novel missense
mutation substituting Cys (TGT) for Arg474 (CGT) that is a highly conserved
amino acid residue among the related proteins. This missense mutation
cosegregated with the type I PS deficiency in this family. Transient
expression studies showed that the secretion of the recombinant Cys-mutant
PS was markedly decreased compared with that of the recombinant wild-type
PS, reproducing the observed phenotype of type I deficiency. Stable
expression and pulse-chase experiments demonstrated an intracellular
degradation and an impaired secretion of the recombinant Cys-mutant PS.
Furthermore, the substitution of Arg474 by Ala or Glu, but not by Lys,
markedly reduced the secretion of the recombinant PS mutants in transient
expression studies, suggesting that a positively charged basic amino acid
might be needed at residue 474 and might play a key role in the protein
structure and conformation of the sex hormone binding globulin-homology
domain of the PS molecule. We postulate that the loss of the highly
conserved Arg474 might be responsible for the type I PS deficiency
inherited in this family.
Volume 87,
Issue 11,
pp. 4643-4650,
06/01/1996
Copyright © 1996 by The American Society of Hematology
