Identification of protein Sα gene mutations including four novel mutations in eight unrelated patients with protein S deficiency

Summary Eight distinct and potentially causative mutations were identified in eight unrelated Japanese patients with protein S (PS) deficiency, by direct DNA sequencing of the protein S α (PS α ) gene‐specific polymerase chain reaction products of all 15 exons and exon/intron boundaries. There were five missense mutations, including two novel mutations (Cys80Tyr and Arg314His), and three showed a major impact on the expected gene products: novel mutations of a 5‐bp deletion (delCTCTG887:Cys206Stop) and a nonsense mutation (Glu208Stop), as well as a previously reported splice site (exon 10 +5 A→G) mutation. One of the patients showed compound heterozygosity for delCTCTG887 and 732A→G. Investigation for the cosegregation state of these two mutations with PS deficiency in the patient's family suggested that the delCTCTG887 mutation was responsible for the abnormal phenotype and that the 732A→G (Lys155Glu) mutation did not appear to play a key role. However, we also identified the same 732A→G (Lys155Glu) mutation in an unrelated patient with apparent PS deficiency with severe pulmonary embolism, and found that this mutation seemed to cosegregate with a PS‐deficient state in her family members. These data implied that unknown factor(s) other than the 732A→G mutation itself might influence phenotypic expression of PS status in different individuals.