Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034065 (pulmonary embolism)
 14,979 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Objective: To observe the clinical feature of familiar hereditary protein S deficiency(HPSD), and to explore the related gene mutations. Methods: A total of seven family members were enrolled in this study and examined during the June to September 2015. Medical histories of the families were analyzed to detect HPSD according to the diagnostic criteria. PROS1 genes of the proband and her family were analyzed. DNA was extracted from peripheral blood. The 15 exons and their intron-exon boundaries of PROS1 were amplified with PCR, and the PCR products were sequenced and analyzed to identify potential mutations. Medical histories from the family members died prior this study were also obtained. Results: Four out of 7 family members of 2 generations were diagnosed as HPSD. The proband suffered from pulmonary embolism, her elder brother suffered from cerebral infarction and her niece suffered from deep vein thrombosis. A missense mutation at the 1063 bp of cDNA(c.1063C>T)was detected in the exon 10 of PROS1, which resulted in arginine 355 to cysteine replacement in the first ball domain of laminin of the protein S(p.R355C). Conclusion: HPSD is an autosomal dominant genetic disease, patients often suffer from recurring vein thrombosis and pulmonary embolism. A missense mutation(c.1063C>T, p. R355C)of PROS1 was discovered in this Chinese family with HPSD, thus, this mutation might be the genetic basis responsible for these family members with HPSD .
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PMID:[Pedigree survey in a family with hereditary protein S deficiency]. 2766 77

Protein S is a vitamin K-dependent plasma glycoprotein that acts as an anticoagulant, and its deficiency usually predisposes individuals to venous thromboembolism. Hereditary protein S deficiency is an autosomal dominant disorder caused by a PROS1 mutation. Herein, we described a novel PROS1 frameshift mutation, c.74dupA, in a hereditary protein S deficiency family. Interestingly, both of the proband and his mother carried the mutation and had a protein S deficiency, however, only the proband suffered a pulmonary embolism while his mother had no history of any thrombosis, suggesting that a triggering event might have been involved in the thrombus formation. Therefore, genetic testing of PROS1 appeared important for the early diagnosis of hereditary protein S deficiency, and it allowed the application of prophylactic interventions to prevent the incidence of severe thrombosis.
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PMID:A novel PROS1 mutation, c.74dupA, was identified in a protein S deficiency family. 2784 49

Protein S (PS) deficiency is associated with a 10-fold increased risk of venous thromboembolism (VTE), but its diagnosis is quite difficult and complicated. In this study, we identified 53 unrelated pedigrees with PS deficiency in China. Data of their clinical characteristics and laboratory examinations were collected. Genetic analysis of PROS1 including direct sequencing, copy number variant detection and messenger ribonucleic acid analysis was performed in probands and related family members. Of these 53 probands, 52.8% (28/53) experienced multi-site and/or recurrent thrombotic episodes, mainly manifested as deep venous thrombosis and/or pulmonary embolism (82.7%). Additional risk factors of VTE were observed in 39.6% (21/53) probands who exhibited a significantly higher rate of recurrent VTE compared with those not, in which 7 probands were complicated by anti-phospholipid syndrome. Most probands and family members exhibited quantitative PS deficiency with impairment of both activated protein C and tissue factor pathway inhibitor cofactor activities. Note that 87.2% (34/39) PROS1 detectable mutation rate was obtained through comprehensive phenotypic and genetic analysis. A total of 36 PROS1 causative mutations including 16 novel mutations were identified in 48 probands, whereas no PROS1 mutations were detected in the other 5 probands. Three hotspot mutations (Glu67Ala, Arg561Trp and Tyr560*) were identified in the Chinese population for the first time. This article provides a framework for correlating the clinical pathogenesis of PS deficiency to genetic backgrounds in the Chinese population.
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PMID:Clinical Manifestation and Mutation Spectrum of 53 Unrelated Pedigrees with Protein S Deficiency in China. 3066 59

Deep vein thrombosis and pulmonary embolism, collectively defined as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Common genetic variants conferring increased varying degrees of VTE risk have been identified by genome-wide association studies (GWAS). Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 result in perinatal lethal thrombosis in homozygotes and markedly increased VTE risk in heterozygotes. However, currently described VTE variants account for an insufficient portion of risk to be routinely used for clinical decision making. To identify new rare VTE risk variants, we performed a whole-exome study of 393 individuals with unprovoked VTE and 6114 controls. This study identified 4 genes harboring an excess number of rare damaging variants in patients with VTE: PROS1, STAB2, PROC, and SERPINC1. At STAB2, 7.8% of VTE cases and 2.4% of controls had a qualifying rare variant. In cell culture, VTE-associated variants of STAB2 had a reduced surface expression compared with reference STAB2. Common variants in STAB2 have been previously associated with plasma von Willebrand factor and coagulation factor VIII levels in GWAS, suggesting that haploinsufficiency of stabilin-2 may increase VTE risk through elevated levels of these procoagulants. In an independent cohort, we found higher von Willebrand factor levels and equivalent propeptide levels in individuals with rare STAB2 variants compared with controls. Taken together, this study demonstrates the utility of gene-based collapsing analyses to identify loci harboring an excess of rare variants with functional connections to a complex thrombotic disease.
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PMID:Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease. 3245 82