scholarly journals A novel rare c.-39C>T mutation in the PROS1 5′UTR causing PS deficiency by creating a new upstream translation initiation codon

2020 ◽  
Vol 134 (10) ◽  
pp. 1181-1190
Author(s):  
Sylvie Labrouche-Colomer ◽  
Omar Soukarieh ◽  
Carole Proust ◽  
Christine Mouton ◽  
Yoann Huguenin ◽  
...  
Keyword(s):  
Protein S ◽  
Upstream Open Reading Frame ◽  
Start Codon ◽  
Molecular Defect ◽  
Reading Frame ◽  
Rare Mutations ◽  
S Deficiency ◽  
Increased Risk ◽  
Sequencing Strategy ◽  
Translation Initiation Codon

Abstract Autosomal dominant inherited Protein S deficiency (PSD) (MIM 612336) is a rare disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with seven PSD affected members in whom no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via an multiplex ligation-dependent probe amplification (MLPA) approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG→ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated in HeLa cells that the variant generates a novel overlapping upstream open reading frame (uORF) and inhibits the translation of the wild-type PS. This work describes the first example of 5′UTR PROS1 mutation causing PSD through the creation of an uORF, a mutation that is not predicted to be deleterious by standard annotation softwares, and emphasizes the need for better exploration of such type of non-coding variations in clinical genomics.

scholarly journals A novel rare c. -39C>T mutation in the PROS1 5’UTR causing PS deficiency by creating a new upstream translation initiation codon and inhibiting the production of the natural protein

2020 ◽  
Author(s):  
Sylvie Labrouche-Colomer ◽  
Omar Soukarieh ◽  
Carole Proust ◽  
Christine Mouton ◽  
Yoann Huguenin ◽  
...  
Keyword(s):  
Protein S ◽  
Start Codon ◽  
Molecular Defect ◽  
Protein S Deficiency ◽  
Wild Type ◽  
Rare Mutations ◽  
S Deficiency ◽  
Increased Risk ◽  
Sequencing Strategy ◽  
Translation Initiation Codon

SummaryInherited Protein S deficiency (PSD) (MIM176880) is a rare automosal dominant disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with 7 PSD affected members in who no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via a MLPA approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG->ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated that the variant generates a novel overlapping ORF and inhibits the translation of the wild type protein from the main ORF in HeLa cells. This work describes the first example of 5’UTR PROS1 mutation causing PSD through the creation of an upstream ORF, a mutation that is not predicted to be deleterious by standard annotation softwares.

Severe Arterial Cerebral Thrombosis in a Patient with Protein S Deficiency (Moderately Reduced Total and Markedly Reduced Free Protein S): A Family Study

1989 ◽  
Vol 61 (01) ◽  
pp. 144-147 ◽  
Author(s):  
A Girolami ◽  
P Simioni ◽  
A R Lazzaro ◽  
I Cordiano
Keyword(s):  
Arterial Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Free Protein ◽  
Her Family ◽  
S Deficiency ◽  
Increased Risk ◽  
Patient Reported

SummaryDeficiency of protein S has been associated with an increased risk of thrombotic disease as already shown for protein C deficiency. Deficiencies of any of these two proteins predispose to venous thrombosis but have been only rarely associated with arterial thrombosis.In this study we describe a case of severe cerebral arterial thrombosis in a 44-year old woman with protein S deficiency. The defect was characterized by moderately reduced levels of total and markedly reduced levels of free protein S. C4b-bp level was normal. Protein C, AT III and routine coagulation tests were within the normal limits.In her family two other members showed the same defect. All the affected members had venous thrombotic manifestations, two of them at a relatively young age. No other risk factors for thrombotic episodes were present in the family members. The patient reported was treated with ASA and dipyridamole and so far there were no relapses.

Elevated Levels of Prothrombin Activation Fragment 1+2 in Plasma from Patients with Heterozygous Arg506 to Gin Mutation in the Factor V Gene (APC-Resistance) and/or Inherited Protein S Deficiency

1996 ◽  
Vol 75 (02) ◽  
pp. 270-274 ◽  
Author(s):  
Benget Zöller ◽  
Johan Holm ◽  
Peter Svensson ◽  
Björn Dahlbäck
Keyword(s):  
Plasma Concentration ◽  
Protein C ◽  
Protein S ◽  
Factor V ◽  
Protein S Deficiency ◽  
Apc Resistance ◽  
S Deficiency ◽  
Increased Risk ◽  
Factor V Gene ◽  
V Gene

SummaryInherited resistance to activated protein C (APC-resistance), caused by a point mutation in the factor V gene leading to replacement of Arg(R)506 with a Gin (Q), and inherited protein S deficiency are associated with functional impairment of the protein C anticoagulant system, yielding lifelong hypercoagulability and increased risk of thrombosis. APC-resistance is often an additional genetic risk factor in thrombosis-prone protein S deficient families. The plasma concentration of prothrombin fragment 1+2 (F1+2), which is a marker of hyper-coagulable states, was measured in 205 members of 34 thrombosis-prone families harbouring the Arg506 to Gin mutation (APC-resistance) and/or inherited protein S deficiency. The plasma concentration of F1+2 was significantly higher both in 38 individuals carrying the FV:Q506 mutation in heterozygous state (1.7 ± 0.7 nM; mean ± SD) and in 48 protein S deficient cases (1.9 ± 0.9 nM), than in 100 unaffected relatives (1.3 ±0.5 nM). Warfarin therapy decreased the F1+2 levels, even in those four patients who had combined defects (0.5 ± 0.3 nM). Our results agree with the hypothesis that individuals with APC-resistance or protein S deficiency have an imbalance between pro- and anti-coagulant forces leading to increased thrombin generation and a hypercoagulable state.

Resolution of possible acquired protein S deficiency after viral suppression in HIV infection

2021 ◽  
Vol 14 (11) ◽  
pp. e244983
Author(s):  
Leigh Cervino ◽  
Jillian Raybould ◽  
Patricia Fulco
Keyword(s):  
Viral Suppression ◽  
Treatment Guidelines ◽  
Protein S ◽  
People Living With Hiv ◽  
Protein S Deficiency ◽  
Anticoagulation Management ◽  
S Deficiency ◽  
Increased Risk ◽  
Undiagnosed Hiv ◽  
Living With Hiv

Current literature suggests an increased risk of venous thromboembolism (VTE) in people living with HIV (PLWH) with poorly controlled viraemia and immunodeficiency. VTE treatment guidelines do not specifically address anticoagulation management in PLWH. We report a case of a 33-year-old woman diagnosed with an unprovoked pulmonary embolism (PE) and deemed protein S deficient. Three years later, she was diagnosed with AIDS. Antiretroviral therapy (ART) was promptly initiated with viral suppression and immune reconstitution within 12 months. Eight years after her initial PE, the patient self-discontinued warfarin. Multiple repeat protein S values were normal. ART without anticoagulation has continued for 3 years with no thrombotic events. This case describes a patient with VTE presumably secondary to undiagnosed HIV with possible consequent acquired protein S deficiency. Additional research is needed to understand the characteristics of PLWH with VTE who may warrant long-term anticoagulation as opposed to shorter courses.

Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1935-1941 ◽  
Author(s):  
Michael Makris ◽  
Michael Leach ◽  
Nick J. Beauchamp ◽  
Martina E. Daly ◽  
Peter C. Cooper ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Protein S ◽  
Structural Defects ◽  
Protein S Deficiency ◽  
Gene Defect ◽  
Thrombotic Risk ◽  
Free Protein ◽  
First Degree Relatives ◽  
S Deficiency ◽  
Increased Risk

Abstract Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1.5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons withPROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.

scholarly journals Deficiency of the natural anticoagulant proteins in women with pregnancy related venous thromboembolism

2009 ◽  
Vol 62 (1-2) ◽  
pp. 53-62 ◽  
Author(s):  
Gorana Mitic ◽  
Ljubica Povazan ◽  
Radmila Lazic ◽  
Dragan Spasic ◽  
Milana Maticki-Sekulic
Keyword(s):  
Venous Thromboembolism ◽  
Protein C ◽  
Protein S ◽  
Single Woman ◽  
Control Group ◽  
Protein S Deficiency ◽  
Clotting Factors ◽  
Protein C Deficiency ◽  
S Deficiency ◽  
Increased Risk

Inherited thrombophilia can be defined as a predisposition to thrombosis caused by heritable defects, such as mutations in genes encoding the natural anticoagulants or clotting factors. Pregnancy related risk of VTE is sixfold increased comparing to non pregnant age matched women. Pregnancy is an independent risk factor for the development of venous thromboembolism and this risk is further increased by the presence of thrombophilia. Aim of the study: The aim of the study was to evaluate the association between deficiency of natural anticoagulants: antithrombin, protein C and protein S and pregnancy related thromboembolism. We have determined the activities of antithrombin, proten C and protein S in 74 women with pregnancy related thrombosis and in 45 healthy women who had at least two uncomplicated pregnancies. Among the women with the history of venous thromboembolism antithrombin deficiency was found in 4 (5.4%), protein C deficiency in 2 (2.7%) and protein S deficiency in 5 (6.76%). The total of 11 (14.6%) women was found to be deficient. Not a single woman in the control group was found to be deficient in natural anticoagulants. Deficiencies of coagulation inhibitors are associated with an increased risk of venous thrombosis during pregnancy and puerperium (p= 0.006). Antithrombin, protein C and protein S deficient women are at higher risk of developing venous thromboembolism during antepartal period (p= 0.0097). Prophylactic treatment with heparin should be recommended from the very beginning of the following pregnancy in women with antithrombin, protein C or protein S deficiency.

scholarly journals The role of hypercoagulability in the development of osteonecrosis of the femoral head

2012 ◽  
Vol 4 (2) ◽  
pp. 17 ◽  
Author(s):  
Marios G. Lykissas ◽  
Ioannis P. Kostas-Agnantis ◽  
Ioannis D. Gelalis ◽  
Georgios Vozonelos ◽  
Anastasios V. Korompilias
Keyword(s):  
Plasminogen Activator ◽  
Lupus Erythematosus ◽  
Protein C ◽  
Activated Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Intravascular Coagulation ◽  
S Deficiency ◽  
Increased Risk ◽  
Von Willebrand

Despite the large number of the outstanding researches, pathogenesis of osteonecrosis remains unknown. During the last decades the hypothesis that increased intravascular coagulation may be the pathogenetic mechanism which leads to osteonecrosis is gaining constantly support. Both primary factors of hypercoagulability, such as resistance to activated protein C, protein C and protein S deficiency, low levels of tissue plasminogen activator, high levels of plasminogen activator inhibitor, von Willebrand factor, lipoprotein (a), and secondary factors of hypercoagulability with factors potentially activating intravascular coagulation, such as pregnancy, antiphospholipid antibodies, systemic lupus erythematosus, hemoglobinopathies and sickle cell disease, and hemato-oncologic diseases are discussed in this article. Although coagulation abnormalities in patients with hip osteonecrosis might represent increased risk factors for the development of bone necrosis by predisposing the patient to thromboembolic phenomena, further investigation is needed to indicate the definite correlation between factors leading to increased intravascular coagulation and pathogenesis of osteonecrosis.

scholarly journals Quality control of transcription start site selection by nonsense-mediated-mRNA decay

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Christophe Malabat ◽  
Frank Feuerbach ◽  
Laurence Ma ◽  
Cosmin Saveanu ◽  
Alain Jacquier
Keyword(s):  
Quality Control ◽  
Rna Polymerase Ii ◽  
Mrna Decay ◽  
Rna Degradation ◽  
Upstream Open Reading Frame ◽  
Start Codon ◽  
Messenger Rnas ◽  
Transcription Start ◽  
Reading Frame ◽  
Nonsense Mediated Mrna Decay

Nonsense-mediated mRNA decay (NMD) is a translation-dependent RNA quality-control pathway targeting transcripts such as messenger RNAs harboring premature stop-codons or short upstream open reading frame (uORFs). Our transcription start sites (TSSs) analysis of Saccharomyces cerevisiae cells deficient for RNA degradation pathways revealed that about half of the pervasive transcripts are degraded by NMD, which provides a fail-safe mechanism to remove spurious transcripts that escaped degradation in the nucleus. Moreover, we found that the low specificity of RNA polymerase II TSSs selection generates, for 47% of the expressed genes, NMD-sensitive transcript isoforms carrying uORFs or starting downstream of the ATG START codon. Despite the low abundance of this last category of isoforms, their presence seems to constrain genomic sequences, as suggested by the significant bias against in-frame ATGs specifically found at the beginning of the corresponding genes and reflected by a depletion of methionines in the N-terminus of the encoded proteins.

scholarly journals Expression and localization of LEF-11 in Autographa californica nucleopolyhedrovirus-infected Sf9 cells

2001 ◽  
Vol 82 (9) ◽  
pp. 2289-2294 ◽  
Author(s):  
Guangyun Lin ◽  
Jeffrey M. Slack ◽  
Gary W. Blissard
Keyword(s):  
Cellular Localization ◽  
Immunofluorescence Microscopy ◽  
Autographa Californica ◽  
Upstream Open Reading Frame ◽  
Upstream Region ◽  
Cell Nuclei ◽  
Reading Frame ◽  
Autographa Californica Nucleopolyhedrovirus ◽  
Late Transcription ◽  
Translation Initiation Codon

The Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) lef-11 gene was found previously to be necessary to support optimal levels of transient expression from an AcMNPV late promoter. The lef-11 gene is unusual in that it overlaps both upstream (orf38) and downstream (pp31) genes. In this study, the expression and cellular localization of LEF-11 were examined. The lef-11 transcripts were detected from 4 to 36 h post-infection (p.i.). The 1·5 kb lef-11 mRNA initiates 196 nt upstream of the lef-11 translation initiation codon, within the upstream orf38 gene. This relatively long 5′ upstream region encodes a potential small upstream open reading frame (ORF) of 58 amino acids that overlaps the lef-11 ORF. The 3′ end of the lef-11 mRNA was mapped as co-terminal with mRNAs from the downstream pp31 gene. Using affinity purified anti-LEF-11 antibodies, levels of LEF-11 expression were found to be maximal between approximately 8 and 24 h p.i., although LEF-11 could be detected as late as 72 h p.i. Using immunofluorescence microscopy, it was determined that LEF-11 localized to dense regions of infected cell nuclei, consistent with its role as a possible late transcription factor.

scholarly journals Upstream Open Reading Frame Mediated Translation of WNK8 Is Required for ABA Response in Arabidopsis

2021 ◽  
Vol 22 (19) ◽  
pp. 10683
Author(s):  
Zhiyong Li ◽  
Yajuan Fu ◽  
Jinyu Shen ◽  
Jiansheng Liang
Keyword(s):  
Open Reading Frame ◽  
Negative Regulator ◽  
Upstream Open Reading Frame ◽  
Start Codon ◽  
Aba Signaling ◽  
Glucose Response ◽  
Reading Frame ◽  
Downstream Target ◽  
Wide Range ◽  
Aba Response

With no lysine (K) (WNK) kinases comprise a family of serine/threonine kinases belonging to an evolutionary branch of the eukaryotic kinome. These special kinases contain a unique active site and are found in a wide range of eukaryotes. The model plant Arabidopsis has been reported to have 11 WNK members, of which WNK8 functions as a negative regulator of abscisic acid (ABA) signaling. Here, we found that the expression of WNK8 is post-transcriptionally regulated through an upstream open reading frame (uORF) found in its 5′ untranslated region (5′-UTR). This uORF has been predicted to encode a conserved peptide named CPuORF58 in both monocotyledons and dicotyledons. The analysis of the published ribosome footprinting studies and the study of the frameshift CPuORF58 peptide with altered repression capability suggested that this uORF causes ribosome stalling. Plants transformed with the native WNK8 promoter driving WNK8 expression were comparable with wild-type plants, whereas the plants transformed with a similar construct with mutated CPuORF58 start codon were less sensitive to ABA. In addition, WNK8 and its downstream target RACK1 were found to synergistically coordinate ABA signaling rather than antagonistically modulating glucose response and flowering in plants. Collectively, these results suggest that the WNK8 expression must be tightly regulated to fulfill the demands of ABA response in plants.

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