IDENTIFICATION OF 8 POINT MUTATIONS IN PROTEIN-S DEFICIENCY TYPE-I - ANALYSIS OF 15 PEDIGREES

We describe molecular genetic studies of 15 patients with protein S de ficiency type I (i. e. reduced total protein S antigen). All the exons of the PROS 1 gene were analyzed both by PCR and direct sequencing in all 15 probands. This analysis led to the identification of point mut ations affecting eight individuals, One of these mutations (codon -25, insertion of T) has been described previously in a Dutch pedigree. Th e other mutations are novel and all are located in exons that code for the protein S domain that is homologous to the steroid hormone bindin g globulins. They include two amino acid replacements (one individual with 340 Gly --> Val, and two individuals with 467 Val --> Gly), and f our frameshift mutations due to either one bp deletions (in codon 261 deletion of T and in codon 267 deletion of G) or insertions (in codon 565 insertion T and after codon 578 insertion of C). Studies performed in six families (totalling 43 subjects) showed cosegregation of the g enetic abnormality with reduced plasma protein S levels, and provided genetic evidence for a heterozygous protein S deficiency in 25 of them . The yield of mutations in this study (53%) confirms that the percent age of protein S deficient cases in which a point mutation is found re mains low.