Molecular basis of a hereditary type I protein S deficiency caused by a substitution of Cys for Arg474.
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.[1]References
- Molecular basis of a hereditary type I protein S deficiency caused by a substitution of Cys for Arg474. Yamazaki, T., Katsumi, A., Kagami, K., Okamoto, Y., Sugiura, I., Hamaguchi, M., Kojima, T., Takamatsu, J., Saito, H. Blood (1996) [Pubmed]
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