Protein S inherited qualitative deficiency: novel mutations and phenotypic influence

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Limited knowledge exists regarding mutations causing qualitative Protein S (PS) deficiency.
• The diagnostic accuracy of commercial assays for Type II PROS1 mutations is not well-established.
• The association between these mutations and thrombosis risk remains unclear.

Purpose of the Study:

• To identify PROS1 mutations associated with Type II PS deficiency.
• To evaluate the impact of Type II PS mutations on thrombin generation.
• To assess the diagnostic performance of a PS functional assay for Type II defects.

Main Methods:

• PROS1 gene analysis in 30 probands and 35 relatives with suspected Type II PS deficiency.
• Thrombin generation tests on plasma from 102 individuals (heterozygous carriers of Type II, Type I/III, or PS Herleen mutations, and controls).
• Evaluation of a PS functional assay (Staclot PS) for screening PROS1 Type II defects.

Main Results:

• Mutations, including 12 novel ones, were identified in 90% of probands, explaining the qualitative PS deficiency.
• 78% of relatives with PROS1 mutations exhibited a Type II PS phenotype.
• Activated Protein C (APC) resistance was observed in carriers of Type II and Type I/III mutations, with Type II having a milder effect.

Conclusions:

• A PS functional assay demonstrated efficiency in screening for PROS1 Type II defects, especially in probands.
• Type II mutations significantly influence ex vivo thrombin generation.
• Further research is required to determine if these mutations elevate venous thromboembolism risk.