PROS1 – Hereditary Thrombophilia due to Congenital Protein S Deficiency

Protein S, encoded by PROS1, is a vitamin K-dependent plasma glycoprotein that serves as a cofactor for activated protein C, downregulating coagulation. Heterozygous pathogenic variants in PROS1 cause Hereditary thrombophilia due to congenital protein S deficiency, an autosomal dominant disorder characterized by reduced free and total protein S antigen and increased risk of venous thromboembolism.

Genetic evidence for PROS1 involvement is robust: the PROSIT study identified 38 distinct PROS1 variants across 53 unrelated probands, including missense, nonsense, splice‐site, frameshift, and copy‐number mutations ([PMID:15712227]). Additional sequencing studies reported over 19 point mutations in 19 thrombosis patients ([PMID:8943854]) and founder missense variants such as p.Leu405Pro in Belgian families ([PMID:9690481]). Variant spectrum spans five classes, with recurrent and private alleles observed in diverse populations. One exemplar null allele is c.74dup (p.Asn25LysfsTer14) causing a frameshift and premature stop ([PMID:27846449]).

Segregation analyses in extended pedigrees further support pathogenicity. A 122-member kindred carrying the Gly295Val substitution showed cosegregation of genotype with phenotype in 44 affected relatives and a hazard ratio of 11.5 for thrombosis by age 30 ([PMID:9424998]). Multipoint linkage and mRNA‐based allele exclusion methods confirm autosomal dominant transmission with high penetrance and near‐complete cosegregation in type I deficiency families ([PMID:8854569]).

Functional studies substantiate a loss‐of‐function mechanism. Recombinant expression of Cys80Tyr and Arg275Cys mutants demonstrated markedly impaired secretion (43.8% and 72.3% of wild type) and reduced APC cofactor activity (0–62% of wild type) in COS-1 cells ([PMID:16961607]). Deletion of the SHBG‐like domain impairs C4b-binding protein interaction and secretion ([PMID:8052964]). Binding assays show decreased phospholipid and calcium‐dependent conformational changes for Gla-domain variants, underscoring the requirement of these domains for anticoagulant function ([PMID:12351389]).

Copy-number analyses reveal that gross PROS1 deletions or duplications account for ~33% of point‐mutation-negative cases, highlighting gene dosage as a pathogenic mechanism ([PMID:19466456]). Endoplasmic reticulum‐associated degradation of misfolded PS mutants (e.g., Tyr595Cys) has been characterized, implicating both proteasome‐dependent and independent pathways ([PMID:15893367]).

Collectively, these data fulfill ClinGen criteria for a Definitive gene‐disease relationship: >50 probands, segregation in >44 relatives, and concordant functional assays. PROS1 testing is clinically actionable for diagnosis, risk stratification, and guiding prophylactic anticoagulation. Key take-home: PROS1 pathogenic variants underlie autosomal dominant congenital protein S deficiency with high penetrance and well‐characterized loss-of‐function mechanisms.

References

• Human mutation • 2005 • Molecular diversity and thrombotic risk in protein S deficiency: the PROSIT study PMID:15712227
• Ann Intern Med • 1998 • Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect PMID:9424998
• Blood • 1996 • Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group. PMID:8943854
• J Thromb Haemost • 2006 • In vitro characterization of missense mutations associated with quantitative protein S deficiency. PMID:16961607
• Human genetics • 2009 • Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. PMID:19466456
• Thrombosis research • 2006 • Characterization of endoplasmic reticulum-associated degradation of a protein S mutant identified in a family of quantitative protein S deficiency. PMID:15893367

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