Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type IIIPS deficiency

DNA sequence analysis of the protein S gene (PROS1) in 22 Spanish probands with type I or III PS deficiency, has allowed the identification of 10 diff erent mutations and 2 new sequence variants in 15 probands, Nine of the mut ations, 8 of which are novel, cosegregate with type I or quantitative PS de ficiency in 12 of the 13 pedigrees analyzed. One of these mutations (Q238X) also cosegregates with both type I and III PS-deficient phenotypes coexist ing in a type I/III pedigree. Another mutation identified in a pedigree wit h these two PS phenotypes is the missense mutation R520G, present in the ho mozygous form in the type I propositus and in the heterozygous form in his type III relatives. By contrast, no cosegregating PROS1 mutation has been f ound in any of the six families with only type III phenotypes. Three of the se families, as well as the two families with type I and I/III phenotypes w here no other PROS1 mutation has been identified, segregate the P allele of the S460P variant, although this allele does not always cosegregate with t he deficient phenotype. From these results we conclude that while mutations in PROS1 are the main cause of type I PS deficiency the molecular basis of the type III phenotype is probably more complex, with many cases not being explained by a PROS1 mutation. Hum Mutat 14:30-39, 1999. (C) 1999 Wiley-Li ss, Inc.