Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149871 (deep vein thrombosis)
 12,364 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multifactorial character of thrombotic disease is shown in a Spanish pedigree in which the propositus, with recurrent deep vein thrombosis, inherited the factor V R/Q506 mutation, the prothrombin 20210G/A variant and type III Protein S deficiency. Among 14 relatives carrying one or two of these three risk factors, thrombosis is present in a heterozygote for R/Q506 and in another for 20210G/A, who also had slightly positive antiphospholipid antibodies. Type I PS deficiency was also found in a young asymptomatic woman. PROS1 analysis showed coexistence of type III and type I PS deficiency to be associated with heterozygosity and homozygosity, respectively, for the P460 or PS Heerlen allele of the S/P460 variant. Analysis of PS values in this and other pedigrees segregating this variant revealed that not only free but also mean total PS levels are slightly but significantly lower in the SP460 heterozygotes than in the SS460 homozygotes. These findings strongly suggest a role of the P460 variant in the expression of the PS deficient phenotype.
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PMID:Homozygosity for the protein S Heerlen allele is associated with type I PS deficiency in a thrombophilic pedigree with multiple risk factors. 1066 62

The Protein S Italian Team (PROSIT) enrolled 79 protein S (PS) deficient families and found 38 PROS1 variations (19 novel) in 53 probands. Of these, 23 variants were selected for expression in'vitro, to evaluate their role as possible causative variants. Transient expression showed high secretion levels (>75%) for three variants, which were considered neutral. Seven missense and five nonsense variants showed low (<or=11%) expression levels and were classified as severe defects. Intermediate expression was observed for eight variants, which were evaluated by factor Va inactivation assay in order to be globally classified as severe or intermediate. Based on the cumulative data, the hazard ratio associated with causative variants was 4.9 (95% CI: 1.4-17.7) for deep vein thrombosis and/or pulmonary embolism, 5.1 (95% CI: 1.1-23.9) for superficial thrombophlebitis, and 4.8 (95% CI: 1.8-13.0) for any venous thrombosis. The hazard ratio for deep vein thrombosis and/or pulmonary embolism in carriers of severe defects only was 7.4 (95% CI: 1.6-24.1). PROSIT showed that dysfunctional variants causing PS deficiency are more common than expected and confirmed that PS deficiency is associated with increased thrombotic risk, although risk assessment is complicated by molecular heterogeneity.
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PMID:Molecular diversity and thrombotic risk in protein S deficiency: the PROSIT study. 1571 27

We investigated the molecular basis of type I protein S (PS) deficiency in two unrelated Japanese families, in which both probands developed pulmonary embolism associated with deep vein thrombosis. Nucleotide sequencing of amplified DNA revealed distinct point mutations in the PROS1 gene of the probands, which were designated protein S Sapporo 1 and protein S Sapporo 2. Additional mutations in the PROS1 gene were excluded by DNA sequencing of all exons and intron/exon boundaries. In the 25-year-old Japanese male patient who carried protein S Sapporo 1, we identified a heterozygous A-to-T change in the invariant ag dinucleotide of the acceptor splice site of intron f of the PROS1 gene. This mutation is a novel splice site mutation that impairs normal mRNA splicing, leading to exon 7 skipping, which was confirmed by platelet mRNA analysis. Translation of this mutant transcript would result in a truncated protein that lacks the entire epidermal growth factor-like domain 3 of the PS molecule. In a 31-year-old Japanese male and his younger brother who each carried protein S Sapporo 2, we detected a previously described heterozygous T-to-C transition at nucleotide position 1147 in exon 10 of the PROS1 gene, which predicts an amino acid substitution of tryptophan by arginine at residue 342 in the laminin G1 domain of the PS molecule. Both mutations would cause misfolding of the PS protein, resulting in the impairment of secretion, which is consistent with the type I PS deficiency phenotype.
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PMID:One novel and one recurrent mutation in the PROS1 gene cause type I protein S deficiency in patients with pulmonary embolism associated with deep vein thrombosis. 1686 38

Inherited deficiency of protein S encoded by the PROS1 gene constitutes an important risk factor for deep vein thrombosis (DVT). Nevertheless, although more than 200 deleterious genetic variations in PROS1 have been identified, causative point mutations of PROS1 gene are not detected in approximately half of protein S-deficient families. The present study investigated whether there may exist a large deletion in PROS1 that constitutes a genetic risk factor for Japanese DVT patients. A multiplex ligation-dependent probe amplification analysis was employed to identify the deletions in PROS1 in 163 Japanese patients with DVT. A large gene deletion was identified in one patient who showed 16% protein S activity and did not carry point mutations in PROS1 by DNA sequencing and it was validated by the quantitative PCR method. The deletion spanned at least the whole PROS1 gene (107 kb) and at most from the centromere located downstream of PROS1, to before the D3S3619 marker, the first heterozygous marker in the upstream of PROS1 in chromosome 3. In conclusion, a large deletion in PROS1 was shown to partly account for DVT with protein S deficiency. Screening for large deletions in PROS1 might be warranted in PROS1 causative point mutation-negative DVT patients with protein S deficiency.
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PMID:A large deletion of the PROS1 gene in a deep vein thrombosis patient with protein S deficiency. 1793 2

Protein S (PS) is a member of the vitamin K-dependent protein family containing similar gamma-carboxyglutamic acid (Gla) domains, although only PS has a thrombin-sensitive region (TSR), which is located between the Gla domain and the first epidermal growth factor-like domain. In this study, a novel PROS1 mutation was identified at the last nucleotide in intron C (c.260-1G>A) in a patient suffering from recurrent deep vein thrombosis associated with PS deficiency. To investigate the molecular mechanisms of PS deficiency caused by the novel PROS1 mutation, we characterized the mutant mRNA, and the secretion and function of the mutant PS molecule associated with the mutation. RT-PCR was used to detect the aberrant mRNA in the patient's platelets, the amount of which was markedly reduced and lacked the region corresponding to exon 4 coding the TSR of the PS molecule. The recombinant mutant PS lacking the TSR (TSR-lack PS) showed a markedly reduced transient expression/secretion level, 37.9% of that of wild-type (WT) PS. Activated protein C (APC) cofactor activity assay showed that TSR-lack PS had no cofactor activity. Moreover, binding assays of monoclonal antibodies recognizing the PS Gla domain and the Gla residues indicated that the bindings of TSR-lack PS to both of these antibodies were clearly weaker than those of WT PS. These findings suggest that the novel mutation leading to the absence of the TSR not only affected the secretion of mutant PS, but was also responsible for impairment of the Gla domain conformation required for the gamma-carboxylation to express APC cofactor activity.
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PMID:A novel splice site mutation in intron C of PROS1 leads to markedly reduced mutant mRNA level, absence of thrombin-sensitive region, and impaired secretion and cofactor activity of mutant protein S. 2002 58

Pregnant women show a low level of protein S (PS) in plasma, which is known to be a risk for deep venous thrombosis. 17Beta-estradiol (E(2)), an estrogen that increases in concentration in the late stages of pregnancy, regulates the expression of various genes via the estrogen receptor (ER). Here, we investigated the molecular mechanisms behind the reduction in PS levels caused by E(2) in HepG2-ERalpha cells, which stably express ERalpha, and also the genomic ER signaling pathway, which modulates the ligand-dependent repression of the PSalpha gene (PROS1). We observed that E(2) repressed the production of mRNA and antigen of PS. A luciferase reporter assay revealed that E(2) down-regulated PROS1 promoter activity and that this E(2)-dependent repression disappeared upon the deletion or mutation of two adjacent GC-rich motifs in the promoter. An electrophoretic mobility shift assay and DNA pulldown assay revealed that the GC-rich motifs were associated with Sp1, Sp3, and ERalpha. In a chromatin immunoprecipitation assay, we found ERalpha-Sp protein-promoter interaction involved in the E(2)-dependent repression of PROS1 transcription. Furthermore, we demonstrated that E(2) treatment recruited RIP140 and the NCoR-SMRT-HDAC3 complex to the PROS1 promoter, which hypoacetylated chromatin. Taken together, this suggested that E(2) might repress PROS1 transcription depending upon ERalpha-Sp1 recruiting transcriptional repressors in HepG2-ERalpha cells and, consequently, that high levels of E(2) leading to reduced levels of plasma PS would be a risk for deep venous thrombosis in pregnant women.
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PMID:Down-regulation of PROS1 gene expression by 17beta-estradiol via estrogen receptor alpha (ERalpha)-Sp1 interaction recruiting receptor-interacting protein 140 and the corepressor-HDAC3 complex. 2020 Jan 60

Hereditary protein S (PS) deficiency (Gene ID: 5627; MIM # 176880) is a notable risk factor for recurrent venous thrombosis, inherited as an autosomal-dominant trait, either homozygous or heterozygous. It may be caused by point mutations in the gene (PROS1) encoding PS, which contains 15 exons on the chromosome 3q11.2. Only a few point mutations associated with the PROS1 gene in patients with hereditary PS deficiency have been reported. A 60-year-old woman was admitted for deep vein thrombosis (DVT) of the right lower extremity. Upon coagulation examination, both the free PS antigen level and the total PS antigen level were decreased, so the DNA-PCR products of all 15 exons, including the exon-intron boundaries of the PROS1, gene were directly sequenced. A substitution from guanine to adenine at position +5 of the donor splice site of intron 10 (c.1155+5G>A) was identified. Further familial study was performed, and the patient's older sister was revealed to have the same mutation; she was already taking warfarin due to diagnosed pulmonary thromboembolism. Here we report a G to A transition at position +5 of intron 10 from the splice donor site as a rare case of a patient with type I hereditary PS deficiency in Korea.
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PMID:A rare splicing mutation in the PROS1 gene of a Korean patient with type I hereditary protein S deficiency. 2216 12

Genetic predisposition of thromboembolism depends on the racial background. Factor V Leiden (G1691A) and factor II mutation (G20210A) are the leading causes of inherited thrombophilias in Caucasians, but are not found in Asian ancestries. Protein S (PS), protein C (PC) and antithrombin (AT) activity are reportedly low in 65% of adult Japanese patients with deep vein thrombosis. Approximately half of the patients with each deficiency carry the heterozygous mutation of PS (PROS1; 20%), PC (PROC; 10%), and AT genes (SERPINC1: 5%). Recently, several studies have revealed an outline of inherited thrombophilias in Japanese children. Congenital thrombophilias in 48 patients less than age 20 years consisted of 45% PC deficiency, 15% PS deficiency and 10% AT deficiency, along with other causes. All PS- and AT-deficient patients had a heterozygous mutation of the respective gene. On the other hand, PC-deficient patients were considered to carry the homozygous or compound heterozygous mutation in 50%, the heterozygous mutation in 25%, and unknown causes in the remaining 25% of patients. Half of unrelated patients with homozygous or compound heterozygous PROC mutations carried PC-nagoya (1362delG), while their parents with its heterozygous mutation were asymptomatic. Most of the PC-deficient patients developed intracranial lesion and/or purpura fulminans within 2 weeks after birth. Non-inherited PC deficiency also conveyed thromboembolic events in early infancy. The molecular epidemiology of thrombosis in Asian children would provide a clue to establish the early intervention and optimal anticoagulant therapy in pediatric PC deficiency.
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PMID:Protein C deficiency as the major cause of thrombophilias in childhood. 2352 Oct 84

Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins, that act as natural anticoagulants. The proteolytic activation of PC by thrombin occurs on the surface of endothelial cells and involves thrombomodulin and endothelial PC receptor. In the presence of PS, phospholipids and calcium, activated PC (APC) inactivates membrane bound factors V (FVa) and FVIIIa by their cleavage at the specific arginine residues. PC and PS deficiencies are inherited as autosomal dominant disorders associated with recurrent venous thromboembolism (VTE) and, in most cases, derived from heterozygous missense mutations (78% and 63%, respectively). Heterozygous PC deficiency is found in 6% of families with inherited thrombophilia, in 3% of patients with a first-time deep vein thrombosis (DVT) and 0.2-0.3% of healthy individuals. The PS deficiency is detected more commonly than PC deficiency and its prevalence has been estimated with a less than 0.5% in the general European population and 2% to 12% of selected groups of thrombophilic patients. Approximately 75% of PC-deficient patients have type I deficiency and 95% of PS-deficient patients develop type I and type III of PS deficiency. The diagnosis of PC and PS deficiencies is challenging, many preanalytical and analytical factors may affect the PC/PS levels. Molecular analysis of the PC and PS genes (PROC and PROS1, respectively) involves direct gene sequencing and if negative, multiplex ligation-dependent probe amplification (MLPA) method. Patients with low PC and PS levels and the known mutation within PROC or PROS1 genes combined with other genetic or environmental thrombosis factors are at increased risk of recurrent thromboembolic events and require lifelong oral anticoagulation.
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PMID:Protein C and protein S deficiency - practical diagnostic issues. 2398 5

Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33-5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT.
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PMID:Single Nucleotide Variant rs2232710 in the Protein Z-Dependent Protease Inhibitor (ZPI, SERPINA10) Gene Is Not Associated with Deep Vein Thrombosis. 2698 41


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