A MUTATION OF THE ACTIVE PROTEIN-S GENE LEADING TO AN EGF1-LACKING PROTEIN IN A FAMILY WITH QUALITATIVE (TYPE-II) DEFICIENCY

The genomic analysis of a 20-year-old man with recurrent deep venous t hrombosis having a protein S (PS)-deficient phenotype corresponding to both type III and type II evidenced two different mutations: a +5 g-- >a mutation in the donor splice site of intron e (ivs e) and a ser 460 to Pro mutation. The propositus' son, who had a type II PS deficiency phenotype, only bore the ivs e +5 g-->a mutation. The study of platel et PS mRNA prepared from this subject showed that the ivs e, +5 g-->a mutation led to the generation of two abnormal transcripts, one lackin g exon 5 and the other lacking exons 5 and 6. The presence of an addit ional PS band with a decreased molecular mass on immunoblots performed in reducing conditions suggested the presence of truncated PS lacking EGF1 (encoded by exon 5). Two monoclonal antibodies (MoAbs) were used to further characterize the nonfunctional plasma PS. Comparison of PS levels measured with each of these MoAbs and PS levels in conventiona l assays was consistent with the presence of an abnormal inactive prot ein in the plasma of both patients bearing the ivs e, +5 g-->a mutatio n, suggesting that variant PS lacking EGF1 is secreted but is devoid o f activated protein C cofactor activity. (C) 1998 by The American Soci ety of Hematalogy.