Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PROS1
Cytogenetic location: 3q11.1 Genomic coordinates (GRCh38): 3:93,873,051-93,973,896 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q11.1 | Thrombophilia 5 due to protein S deficiency, autosomal dominant | 612336 | Autosomal dominant | 3 |
| Thrombophilia 5 due to protein S deficiency, autosomal recessive | 614514 | Autosomal recessive | 3 |
Protein S is a vitamin K-dependent plasma protein that inhibits blood clotting by serving as a nonenzymatic cofactor for activated protein C (PROC; 612283) in the inactivation of procoagulant factors V (F5; 612309) and VIII (F8; 300841). Protein S exists in 2 forms in plasma: the free, functionally active form, and the inactive form complexed with C4b-binding protein (C4BPA; 120830) (Dahlback and Stenflo, 1981).
Lundwall et al. (1986) isolated and sequenced cDNA clones for protein S. Human protein S is a single-chain protein of 635 amino acids with 82% homology to bovine protein S. Hoskins et al. (1987) isolated cDNA for a protein S precursor.
Edenbrandt et al. (1990) isolated clones corresponding to the 3-prime part of the PROS1 gene, including the thrombin (F2; 176930)-sensitive region, 4 domains that are homologous to the epidermal growth factor (EGF; 131530) precursor, the COOH-terminal part of protein S that is homologous to a plasma sex hormone binding globulin (SHBG; 182205), and the 3-prime untranslated region.
Schmidel et al. (1990) determined that the PROS1 gene contains 15 exons and spans more than 80 kb.
By Southern blot analysis of DNA from somatic cell hybrids, Naylor et al. (1987) and Long et al. (1988) assigned the protein S gene to chromosome 3p21-q21. By study of somatic cell hybrids with cDNA probes, including hybrids with rearranged chromosomes, Watkins et al. (1987, 1988) assigned the protein S gene to 3p21-q21; see Stanislovitis et al. (1987).
By in situ hybridization, Watkins et al. (1988) assigned the PROS gene to chromosome 3p11.1-q11.2, the region immediately surrounding the centromere.
Hartz (2008) mapped the PROS1 gene to chromosome 3q11.2 based on an alignment of the PROS1 sequence (GenBank AK292994) with the genomic sequence (build 36.1).
Pseudogene
By Southern analysis of the protein S locus, with cDNA probes encompassing the 3-prime untranslated region of protein S mRNA, Ploos van Amstel et al. (1987) determined that there are 2 protein S genes, both situated on chromosome 3. Conservation of restriction sites suggested that the 2 genes are highly homologous.
Ploos van Amstel et al. (1988) reported the nucleotide sequence of the complete 3-prime untranslated regions of the 2 protein S genes, which they designated PS-alpha (PSA) and PS-beta (PSB). Comparison of the 2 genes with the reported protein S liver cDNAs showed that the latter all originated from the PSA gene. Therefore, PSA appeared to be the major locus for synthesis of liver protein S mRNA.
Edenbrandt et al. (1990) isolated and mapped genomic clones corresponding to the protein S beta-gene, which was found to contain stop codons and a 2 bp-deletion introducing a frameshift, suggesting that it is a pseudogene.
The protein S beta locus represents a pseudogene (PROSP) on chromosome 3.
In human plasma, around 40% of protein S circulates as a free protein, while the remaining 60% forms a noncovalent 1:1 stoichiometric complex with the beta-chain of the complement C4b-binding protein (C4BPB; 120831) (Dahlback, 1991). This interaction is of high affinity and abolishes the anticoagulant properties of protein S. Therefore, in plasma, only the molar excess of protein S over C4BPB circulates in a free form and is active as a cofactor of activated protein C (APC) in the inactivation of the procoagulant factors Va and VIIIa (Griffin et al., 1992).
Maillard et al. (1992) studied protein S synthesis and secretion by human osteosarcoma cell lines and by normal adult human osteoblast-like cells. They showed that protein S is synthesized by osteoblasts in an active form and incorporated in the mineralized matrix of bone. Previously, protein S was known to be synthesized mostly by hepatocytes.
Heeb et al. (1994) presented data that demonstrated mechanisms of anticoagulant action for protein S that are independent of activated protein C and that involve direct binding to factors Xa and Va and direct inhibition of factor Xa.
Anderson et al. (2003) identified protein S as the factor in serum that mediates serum-stimulated macrophage phagocytosis of apoptotic cells, a process thought to limit the development of inflammation and autoimmune disease. Flow cytometric and competitive inhibition analyses demonstrated that protein S binds exclusively to phosphatidylserine-positive apoptotic cells in a calcium-dependent manner. Anderson et al. (2003) concluded that protein S is a multifunctional protein that facilitates the clearance of early apoptotic cells in addition to regulating blood coagulation.
Fourgeaud et al. (2016) demonstrated that the TAM receptor tyrosine kinases Mer (MERTK; 604705) and Axl (109135) regulate the microglial functions of damage sensing and routine noninflammatory clearance of dead brain cells. Fourgeaud et al. (2016) found that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the central nervous system (CNS), and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 (600441) and protein S. Using live 2-photon imaging, the authors demonstrated that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Fourgeaud et al. (2016) also showed that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson disease (168600). Fourgeaud et al. (2016) concluded that these results established TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.
Autosomal Dominant Thrombophilia due to Protein S Deficiency
Ploos van Amstel et al. (1989) used Southern blot analysis to identify a heterozygous deletion in the PROS1 gene in a patient with familial thrombophilia associated with protein S deficiency (THPH5; 612336). The deletion segregated with the disorder in this family. The findings indicated that this specific disorder is directly the result of a defect in the protein S gene.
Formstone et al. (1995) identified 7 different heterozygous mutations in the PROS1 gene (see, e.g., 176880.0002) in patients with protein S deficiency.
In affected members of 22 Spanish families with protein S deficiency, Espinosa-Parrilla et al. (1999) identified 10 different mutations in the PROS1 gene (see, e.g., 176880.0007; 176880.0008). One of these mutations, Q238X (176880.0007), cosegregated with both type I and type III protein S-deficient phenotypes coexisting in a type I/type III pedigree. By contrast, Espinosa-Parrilla et al. (1999) found no cosegregating PROS1 mutations in any of the 6 families with only type III phenotypes. From these results, Espinosa-Parrilla et al. (1999) concluded that while mutations in PROS1 are the main cause of type I protein S deficiency, the molecular basis of the type III phenotype may be more complex.
Beauchamp et al. (2004) stated that over 200 mutations in the PROS1 gene had been identified in patients with protein S deficiency.
Using multiplex ligation-dependent probe amplification (MLPA) analysis, Pintao et al. (2009) identified copy number variation (CNV) involving the PROS1 gene in 6 (33%) of 18 probands with protein S deficiency who did not have point mutations by direct sequencing. The results were confirmed by PCR analysis. Three probands were found to have complete deletion of the PROS1 gene; all had type I deficiency with quantitative deficiency of total and free PROS1 antigen. Two probands had partial deletion, and 1 proband had partial duplication. Three probands with CNV had positive family history and the CNV cosegregated with protein S deficiency in family members.
Autosomal Recessive Thrombophilia due to Protein S Deficiency
In a Thai infant with autosomal recessive thrombophilia due to protein S deficiency (THPH6; 614514) (Mahasandana et al., 1990), Pung-amritt et al. (1999) identified compound heterozygosity for 2 mutations in the PROS1 gene (176880.0010 and 176880.0011). The patient presented with neonatal purpura fulminans. Each parent, who was found by ELISA studies to have about 50% of protein S free antigen, was heterozygous for 1 of the mutations.
In an infant, born of Albanian parents, with autosomal recessive thrombophilia due to protein S deficiency, Fischer et al. (2010) identified a homozygous mutation in the PROS1 gene (176880.0012). The patient presented with seizures and hemorrhagic shock associated with a massive intracranial bleed and laboratory evidence of disseminated intravascular coagulation. After stabilization, laboratory studies showed thrombophilia due to severe protein S deficiency (less than 10%). Each parent was heterozygous for the mutation and showed about 50% protein S activity.
Burstyn-Cohen et al. (2009) generated several lines of transgenic mice with conditional knockout of the Pros1 gene in (1) all cells, (2) in hepatocytes, (3) in endothelial and hematopoietic cells, and (4) in vascular smooth muscle cells. Complete knockout of Pros1 in all cells was embryonic lethal. Pros1 -/- mice died between E15.5 and E17.5 from massive coagulopathy with large blood clots and associated hemorrhage throughout the body. The embryonic vasculature of Pros1 -/- mice showed defects in vessel development, integrity, and function, with reduction of smooth muscle staining. Pros1 +/- mice showed milder defects in vessel morphology, with permeability defects, and also showed shorter clot times than wildtype, consistent with a prothrombotic state. However, this effect was independent of protein C, suggesting that protein S can inhibit clotting on its own. Vascular smooth muscle-specific Pros1 -/- mice showed mild defects similar to Pros1 +/- mice. Hepatocyte-specific Pros1 -/- mice were viable and had normal vessel morphology, although about 15% showed focal fibrin deposition in blood vessels. Vascular endothelial and hematopoietic cell-specific Pros1 -/- mice were also viable, but had vessel defects. They also had approximately 57% circulating protein S compared to wildtype, indicating that these cells contribute to circulating protein S levels. Burstyn-Cohen et al. (2009) suggested that PROS1 may have a direct anticoagulant function in the blood coagulation cascade as well as a role in vascular development and function, most likely via its ability to bind to and activate TAM receptors, such as AXL (109135).
Saller et al. (2009) found that Pros -/- embryos died late in gestation with consumptive coagulopathy. Pros +/- mice were viable and appeared normal, and they did not present abnormal mortality or signs of thrombosis with age. Pros +/- blood cell counts and plasma levels of coagulation factors were normal, although plasma protein S concentration was half normal. However, Pros +/- mice exhibited reduced plasma activated protein C cofactor (F5) activity, reduced anticoagulant activity, and increased sensitivity to development of tissue factor (F3; 134390)-induced thromboembolism.
Bertina et al. (1990) reported an abnormal protein S that had a slightly lower molecular weight than normal, bound normally to C4BP (120830), and retained full APC-cofactor activity. DNA analysis showed that the abnormality resulted from a T-to-C transition in the PROS1 gene, resulting in a ser460-to-pro (S460P) substitution within a potential glycosylation site. The variant was considered to be a neutral polymorphism and was estimated to be in 0.52% of healthy blood donors. Bertina et al. (1990) suggested that this variant, termed the 'Heerlen variant,' may be identical with the variant reported by Schwarz et al. (1989).
Beauchamp et al. (2004) studied the molecular basis of free protein S deficiency in 7 individuals identified with persistently low plasma protein S levels from a survey of 3,788 Scottish blood donors. Five of the donors were found to be heterozygous for the Heerlen polymorphism. Haplotype analysis indicated a founder effect in 4 of the 5 donors. Beauchamp et al. (2004) estimated the prevalence of heritable protein S deficiency in the Scottish population to be between 0.16 and 0.21%, predominantly resulting from the presence of the Heerlen allele. Although all had persistently decreased free protein S, thrombotic events were not reported.
In affected members of a family with protein S deficiency (THPH5; 612336), Formstone et al. (1995) identified a heterozygous A-to-G transition in exon 8 of the PROS gene, resulting in an asn217-to-ser (N217S) substitution in the fourth EGF domain of protein S.
In a 29-year-old woman with thrombotic disease associated with heterozygous protein S deficiency (THPH5; 612336), Hayashi et al. (1994) identified a heterozygous A-to-G transition in exon 6 of the PROS1 gene, resulting in a lys155-to-glu (K155E) substitution in the second epidermal growth factor-like domain. The patient had normal levels of both total and free protein S antigen, but low cofactor activity for activated protein C, indicating that she had a variant of protein S, referred to as protein S Tokushima. Approximately one-half of the patient's protein S appeared to be the variant with a higher molecular weight than normal. The patient's mother and a maternal aunt also had thrombotic disease. The disorder in this family was classified as type IIb protein S deficiency.
In 2 unrelated individuals with thrombophilia associated with protein S deficiency (THPH5; 612336), Reitsma et al. (1994) identified a heterozygous G-to-A transition at position +5 of the donor splice site consensus sequence of intron 10 of the PROS1 gene.
In 2 unrelated probands with thrombophilia associated with protein S deficiency (THPH5; 612336), Reitsma et al. (1994) identified a heterozygous A-to-T transversion at the wobble position of the stop codon of the PROS1 gene. This led to extension of the normal protein S molecule with 14 amino acids before a novel stop codon was reached. Stop codon 636 was converted to tyr by the A-to-T mutation; the new stop was at codon 649.
In affected individuals of 7 kindreds with thrombophilia associated with protein S deficiency (THPH5; 612336), Beauchamp et al. (1998) identified a heterozygous A-to-G transition 9 bp upstream of exon 12 in intron 11 of the PROS1 gene. In all but 1 case, the mutation caused type I deficiency; 1 individual had type III deficiency. While ectopic transcript analysis using the BstXI dimorphism in exon 15 failed to detect a transcript from the mutated allele, analysis of transcripts spanning exons 11 and 12 revealed a minor mRNA species. Sequencing confirmed that the mutation created a new RNA acceptor site introducing 8 nucleotides of intronic sequence into the mature mRNA. Haplotype analysis of a defective PROS1 allele in 6 families revealed the same haplotype in all affected individuals, suggesting the existence of a common ancestor. Six of the 14 relatives with the mutation experienced at least 1 venous thrombotic event, strongly supporting the association of the mutation with venous thrombosis.
In affected members of 4 families with protein S deficiency (THPH5; 612336), Espinosa-Parrilla et al. (1999) identified a heterozygous 981C-T transition in exon 8 of the PROS1 gene, resulting in a gln238-to-ter (Q238X) substitution.
In affected members of a family with protein S deficiency (THPH5; 612336), Espinosa-Parrilla et al. (1999) identified a heterozygous 1827C-G transversion in exon 14 of the PROS1 gene, resulting in an arg520-to-gly (R520G) substitution.
In affected members of a 3-generation Chinese family with autosomal dominant protein S deficiency (THPH5; 612336), Leung et al. (2010) identified a heterozygous 1063C-T transition in exon 10 of the PROS1 gene, resulting in an arg355-to-cys (R355C) substitution in the first globular domain of protein S. Three individuals with the mutation were symptomatic and had onset of ischemic stroke in their forties. Three additional family members with the mutation were asymptomatic at age 42, 20, and 13 years. Laboratory studies of all mutation carriers showed protein S deficiency type III, with decreased free protein S levels and activity, but normal total protein levels. Brain MRI of all 3 affected individuals and 2 of the asymptomatic individuals showed white matter infarctions in the internal and external border zones, with some extension into the paraventricular white matter regions in those with higher infarct volume. The cerebral cortex was spared. The findings indicated that protein S deficiency induces a hypercoagulable state that predisposes to arteriolar thrombosis in certain regions of the cerebral vasculature.
In a Thai infant with autosomal recessive thrombophilia due to protein S deficiency (THPH6; 614514), Pung-amritt et al. (1999) identified compound heterozygosity for 2 mutations in the PROS1 gene: a 1-bp insertion in exon 6 (146insA), resulting in a frameshift and premature termination at residue 155, and a C-to-T transition in exon 12, resulting in an arg410-to-ter (R410X; 176880.0011) substitution. Each parent, who had about 50% of protein S free antigen, was heterozygous for 1 of the mutations. The patient, who was first reported by Mahasandana et al. (1990), presented at age 10 days with neonatal purpura fulminans and later developed disseminated intravascular coagulation, which responded to cryoprecipitate transfusion. She was found to have endophthalmitis and was blind, suggesting retinal vessel thrombosis in utero. Protein S was almost undetectable in the patient's plasma. The family history was negative for thrombosis.
For discussion of the arg410-to-ter (R410X) mutation in the PROS1 gene that was found in compound heterozygous state in an infant with autosomal recessive thrombophilia due to protein S deficiency (THPH6; 614514) by Pung-amritt et al. (1999), see 176880.0010.
In an infant, born of Albanian parents, with autosomal recessive thrombophilia due to protein S deficiency (THPH6; 614514), Fischer et al. (2010) identified a homozygous 701A-G transition in the PROS1 gene, resulting in a tyr234-to-cys (Y234C) substitution. The patient presented on the fourth day of life with seizures and hemorrhagic shock associated with a massive intracranial bleed and laboratory evidence of disseminated intravascular coagulation. After stabilization, laboratory studies showed thrombophilia due to severe protein S deficiency (less than 10% activity). The infant later developed acute arterial thrombosis of the aorta and died on the eighth day of life. Postmortem examination showed diffuse thromboses of intracerebral capillaries, suggesting that the underlying prothrombotic condition resulted in hemorrhage. Each parent was heterozygous for the mutation and showed about 50% protein S activity.
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Beauchamp, N. J., Daly, M. E., Makris, M., Preston, F. E., Peake, I. R. A novel mutation in intron K of the PROS1 gene causes aberrant RNA splicing and is a common cause of protein S deficiency in a UK thrombophilia cohort. Thromb. Haemost. 79: 1086-1091, 1998. [PubMed: 9657428]
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