Protein S deficiency is an autosomal dominant disorder that results from mutations in the protein S gene (PROS1). Inherited deficiency of protein S constitutes a risk factor for venous thromboembolism. Protein S functions as a nonenzymatic cofactor for activated protein C in the proteolytic degradation of coagulation factors Ⅴa and Ⅷa. The frequency of protein S deficiency seems to differ between populations. More than 200 rare mutations in PROS1 have been identified in patients with protein S deficiency. Among the prevalent mutations within PROS1, the S460P substitution (known as Heerlen polymorphism) detected in Caucasians and the K196E substitution (known as protein S Tokushima) found in Japanese have been intensively studied for their structures and potential functions in the disorder of protein S deficiency. Until now, causative mutations in PROS1 have been found in only approximately 50% of cases with protein S deficiency. Co-segregation analysis of microsatellite haplotypes with protein S deficiency
in families with protein S deficiency suggests that the causative defects in the PROS1 mutation-negative patients are located in or close to the PROS1 gene. Large PROS1 gene deletions have been identified in 3 out of 9 PROS1 mutation-negative Swedish VTE families with
protein S deficiency and 1 out of 6 PROS1 mutation-negative Japanese patients with protein S deficiency. Intensive sequencing of the entire PROS1 gene, including introns, may be needed to identify the cryptic mutations in those patients, and these efforts might uncover the pathogenesis of protein S deficiency.