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 (PSI deficiency was investigated. DNA sequence analysis in the proband showed a novel missense mutation substituting Cys (7I3T) for Arg474 (CGT) that is a highly conserved amino acid residue among the related proteins. This missense mu-tation cosegregated with the type I PS deficiency in this family. Transient expression studies showed that the secre-tion of the recombinant Cys-mutant PS was markedly de-creased compared with that of the recombinant wild-type PS, reproducing the observed phenotype of type I deficiency. Stable expression and pulse-chase experiments demon-strated an intracellular degradation and an impaired secre-ROTEIN S (PS) IS A plasma glycoprotein that functions P as an important natural anticoagulant. PS serves as a cofactor for activated protein C (APC) in the protein C path-way, ‘ which regulates blood coagulation by inactivating fac