Two Distinct Novel Splice Site Mutations in a Compound Heterozygous Patient with Protein S Deficiency

1997 ◽  
Vol 77 (01) ◽  
pp. 014-020 ◽  
Author(s):  
Tomio Yamazaki ◽  
Akira Katsumi ◽  
Yoshihiro Okamoto ◽  
Toshio Takafuta ◽  
Shinobu Tsuzuki ◽  
...  
Keyword(s):  
Splice Site ◽  
Protein S ◽  
Mutant Protein ◽  
Compound Heterozygous ◽  
Protein S Deficiency ◽  
Acceptor Splice Site ◽  
Mrna Accumulation ◽  
S Deficiency ◽  
Heterozygous Patient

SummaryGenetic analysis revealed two distinct novel splice site mutations in a compound heterozygous patient with protein S deficiency. The paternal mutation was a G-to-T transition at position -1 of the acceptor splice site of intron N (Mutation I), and the maternal mutation was a G-to-C transversion at position -1 of the donor splice site of intron C (Mutation II). Both splice site mutations decreased the mutated mRNA accumulation to the same extent, approximately 40% of the normal mRNA. However, the mutations were associated with different phenotypical expressions: the paternal mutant protein S was not detected in vivo, while the maternal mutant protein S was present in the plasma in reduced quantity. Because Mutation I caused a cryptic splicing in the mutated mRNA, resulting in a reading frameshift and premature termination, the predicted mutant protein S might be highly unstable. In contrast, Mutation II led to the substitution of Val46 by Leu, which might be much less deleterious for the synthesis, secretion and stability of the predicted mutant protein S. It was supposed that the different post-translational metabolisms produced the distinct phenotypical expressions of the mutations.

scholarly journals A hitherto unknown splice site defect in the protein S gene (PROS1): the mutation results in allelic exclusion and causes type I and type III protein S deficiency

1997 ◽  
Vol 99 (2) ◽  
pp. 298-300 ◽  
Author(s):  
Stefan Mustafa ◽  
Ingrid Pabinger ◽  
Katalin Varadi ◽  
Walter-Michael Halbmayer ◽  
Klaus Lechner ◽  
...  
Keyword(s):  
Splice Site ◽  
Protein S ◽  
Allelic Exclusion ◽  
Type I ◽  
Protein S Deficiency ◽  
Type Iii ◽  
S Gene ◽  
S Deficiency

scholarly journals Detection and characterization of seven novel protein S (PROS) gene lesions: evaluation of reverse transcript-polymerase chain reaction as a mutation screening strategy

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2632-2641 ◽  
Author(s):  
CJ Formstone ◽  
AI Wacey ◽  
LP Berg ◽  
S Rahman ◽  
D Bevan ◽  
...  
Keyword(s):  
Splice Site ◽  
Mutation Screening ◽  
Protein S ◽  
Allelic Exclusion ◽  
Type I ◽  
Protein S Deficiency ◽  
Rt Pcr ◽  
S Deficiency ◽  
Polymerase Chain ◽  
Reverse Transcript

Abstract The molecular genetic analysis of protein S deficiency has been hampered by the complexity of the protein S (PROS) gene and by the existence of a homologous pseudogene. In an attempt to overcome these problems, a reverse transcript-polymerase chain reaction (RT-PCR) mutation screening procedure was developed. However, the application of this mRNA-based strategy to the detection of gene lesions causing heterozygous type I protein S deficiency appears limited owing to the high proportion of patients exhibiting absence of mRNA derived from the mutation-bearing allele (“allelic exclusion”). Nevertheless, this strategy remains extremely effective for rapid mutation detection in type II/III protein S deficiency. Using the RT-PCR technique, a G-to-A transition was detected at position +1 of the exon IV donor splice site, which was associated with type I deficiency and resulted in both exon skipping and cryptic splice site utilization. No abnormal protein S was detected in plasma from this patient. A missense mutation (Asn 217 to Ser), which may interfere with calcium binding, was also detected in exon VIII in a patient with type III protein S deficiency. A further three PROS gene lesions were detected in three patients with type I deficiency by direct sequencing of exon-containing genomic PCR fragments: a single base-pair (bp) deletion in exon XIV, a 2-bp deletion in exon VIII, and a G0to-A transition at position-1 of the exon X donor splice site all resulted in the absence of mRNA expressed from the disease allele. Thus, the RT-PCR methodology proved effective for further analysis of the resulting protein S-deficient phenotypes. A missense mutation (Met570 to Thr) in exon XIV of a further type III-deficient proband was subsequently detected in this patient's cDNA. No PROS gene abnormalities were found in the remaining four subjects, three of whom exhibited allelic exclusion. However, the father of one such patient exhibiting allelic exclusion was subsequently shown to carry a nonsense mutation (Gly448 to Term) within exon XII.

Poor Relationship between Phenotypes of Protein S Deficiency and Mutations in the Protein S Alpha Gene

1999 ◽  
Vol 82 (12) ◽  
pp. 1634-1638 ◽  
Author(s):  
José Hermida ◽  
Pier Mannuccio Mannucci ◽  
Elena Faioni
Keyword(s):  
Splice Site ◽  
Genetic Defect ◽  
Splice Site Mutation ◽  
Protein S ◽  
Nucleotide Sequencing ◽  
Type I ◽  
Protein S Deficiency ◽  
Site Mutation ◽  
Single Strand Conformational Polymorphism ◽  
S Deficiency

SummaryBy single strand conformational polymorphism, nucleotide sequencing and enzyme restriction, we analyzed the protein S α gene in 17 protein S-deficient probands and in their available family members. The relationship between genotype and phenotype was also evaluated. Twelve different sequence variations were identified in 17 probands. Ten were putative causal mutations distributed in 16 probands: 4 were nonsense, 5 missense and one a splice site mutation. In most families in which a mutation was identified, more than one phenotype of PS deficiency was present. The same splice site mutation (intron j G-A, exon 10+5) was associated with type I deficiency in one family and with type I/III in another unrelated family. A phenotypic discrepancy was also observed for the Arg474Pro, Gly597Asp and Arg410stop mutations. Glu26Ala, previously reported in kindreds with type I deficiencies, was found in association with I, II and III phenotypes in four unrelated kindreds. Phenotypic analysis of protein S deficiency is poorly related to the underlying genetic defect.

Vitreoretinal findings similar to retinopathy of prematurity in infants with compound heterozygous protein S deficiency☆

Ophthalmology ◽  
1999 ◽  
Vol 106 (8) ◽  
pp. 1525-1530 ◽  
Author(s):  
Helen A Mintz-Hittner ◽  
Michael J Miyashiro ◽  
Donna M Knight-Nanan ◽  
Ronan E O’Malley ◽  
Richard A Marlar
Keyword(s):  
Retinopathy Of Prematurity ◽  
Protein S ◽  
Compound Heterozygous ◽  
Protein S Deficiency ◽  
S Deficiency

Failure in the Detection of Aberrant mRNA from the Heterozygotic Splice Site Mutant Allele for Protein S in a Patient with Protein S Deficiency

2001 ◽  
Vol 102 (3) ◽  
pp. 187-196 ◽  
Author(s):  
Hiroko Iida ◽  
Mutsuko Nakahara ◽  
Kimihiro Komori ◽  
Masako Fujise ◽  
Machiko Wakiyama ◽  
...  
Keyword(s):  
Splice Site ◽  
Mutant Allele ◽  
Protein S ◽  
Protein S Deficiency ◽  
S Deficiency

scholarly journals Detection and characterization of seven novel protein S (PROS) gene lesions: evaluation of reverse transcript-polymerase chain reaction as a mutation screening strategy

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2632-2641 ◽  
Author(s):  
CJ Formstone ◽  
AI Wacey ◽  
LP Berg ◽  
S Rahman ◽  
D Bevan ◽  
...  
Keyword(s):  
Splice Site ◽  
Mutation Screening ◽  
Protein S ◽  
Allelic Exclusion ◽  
Type I ◽  
Protein S Deficiency ◽  
Rt Pcr ◽  
S Deficiency ◽  
Polymerase Chain ◽  
Reverse Transcript

The molecular genetic analysis of protein S deficiency has been hampered by the complexity of the protein S (PROS) gene and by the existence of a homologous pseudogene. In an attempt to overcome these problems, a reverse transcript-polymerase chain reaction (RT-PCR) mutation screening procedure was developed. However, the application of this mRNA-based strategy to the detection of gene lesions causing heterozygous type I protein S deficiency appears limited owing to the high proportion of patients exhibiting absence of mRNA derived from the mutation-bearing allele (“allelic exclusion”). Nevertheless, this strategy remains extremely effective for rapid mutation detection in type II/III protein S deficiency. Using the RT-PCR technique, a G-to-A transition was detected at position +1 of the exon IV donor splice site, which was associated with type I deficiency and resulted in both exon skipping and cryptic splice site utilization. No abnormal protein S was detected in plasma from this patient. A missense mutation (Asn 217 to Ser), which may interfere with calcium binding, was also detected in exon VIII in a patient with type III protein S deficiency. A further three PROS gene lesions were detected in three patients with type I deficiency by direct sequencing of exon-containing genomic PCR fragments: a single base-pair (bp) deletion in exon XIV, a 2-bp deletion in exon VIII, and a G0to-A transition at position-1 of the exon X donor splice site all resulted in the absence of mRNA expressed from the disease allele. Thus, the RT-PCR methodology proved effective for further analysis of the resulting protein S-deficient phenotypes. A missense mutation (Met570 to Thr) in exon XIV of a further type III-deficient proband was subsequently detected in this patient's cDNA. No PROS gene abnormalities were found in the remaining four subjects, three of whom exhibited allelic exclusion. However, the father of one such patient exhibiting allelic exclusion was subsequently shown to carry a nonsense mutation (Gly448 to Term) within exon XII.

Abstract 548: Molecular Mechanism Behind Protein S Deficiency in Obese Patients

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Vijaya S Pilli
Keyword(s):  
Molecular Mechanism ◽  
Plasma Protein ◽  
Protein S ◽  
Factor Ix ◽  
Negative Regulator ◽  
Liver Protein ◽  
Protein S Deficiency ◽  
S Deficiency ◽  
Increased Risk

Introduction: Protein S is a vitamin K-dependent plasma protein, produced mainly in the liver; Protein S circulates in the blood at a concentration of 450 nM. Protein S is an anticoagulant, serving as a cofactor for APC and TFPI, and as an inhibitor of Factor IX (FIXa). Protein S deficiency causes deep vein thrombosis (DVT), increased risk of inflammation and, because DVT is a complication commonly observed in obese individuals, Protein S deficiency might be associated with obesity. Aim: To identify a correlation between Protein S deficiency and obesity, and identify the probable molecular mechanism behind the Protein S deficiency in the obese subjects. Methods: Immunoblots, ELISA, EMSA, CHIP, aPTT assay, and thrombin generation assay. Results: By ELISA, we measured a decrease in Protein S level in obese mice compared with wild type mice. In obesity, the liver becomes hypoxic, thus, we hypothesized that hypoxia and hypoxia inducible factor 1 alpha (HIF1α) may regulate Protein S expression in obesity. We found that a high fat diet induced HIF1α stability in mice. HIF1α levels were inversely proportional to Protein S levels, suggesting that HIF1α is a negative regulator of Protein S expression. We further identified a putative HIF1α binding site in the Protein S promoter, and, by using in vitro and in vivo assays, we demonstrated that HIF1α binds directly to the Protein S promoter and suppresses transcription. We further confirmed HIF1α-mediated Protein S transcriptional regulation in vivo, Plasma Protein S levels are increased in the liver-specific HIF1α knockout mouse whereas, liver-specific overexpression of HIF1α reduced the concentration of Protein S in the plasma. Conclusion: We conclude that HIF1α regulates Protein S expression in mouse liver and in obesity. Inhibition of HIF1α or intravenous injection of Protein S may reduce the occurrence of DVT in obese individuals.

Compound heterozygous mutations in the PROS1 gene responsible for quantitative and qualitative protein S deficiency

2009 ◽  
Vol 90 (4) ◽  
pp. 537-539
Author(s):  
Jun Yamanouchi ◽  
Takaaki Hato ◽  
Tatsushiro Tamura ◽  
Hiroshi Fujiwara ◽  
Yoshihiro Yakushijin ◽  
...  
Keyword(s):  
Protein S ◽  
Compound Heterozygous ◽  
Protein S Deficiency ◽  
S Deficiency ◽  
Compound Heterozygous Mutations

The Frequency of Type I Heterozygous Protein S and Protein C Deficiency in 141 Unrelated Young Patients with Venous Thrombosis

1988 ◽  
Vol 59 (01) ◽  
pp. 018-022 ◽  
Author(s):  
C L Gladson ◽  
I Scharrer ◽  
V Hach ◽  
K H Beck ◽  
J H Griffin
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Antithrombin Iii ◽  
Young Patients ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Low Protein ◽  
S Deficiency

SummaryThe frequency of heterozygous protein C and protein S deficiency, detected by measuring total plasma antigen, in a group (n = 141) of young unrelated patients (<45 years old) with venous thrombotic disease was studied and compared to that of antithrombin III, fibrinogen, and plasminogen deficiencies. Among 91 patients not receiving oral anticoagulants, six had low protein S antigen levels and one had a low protein C antigen level. Among 50 patients receiving oral anticoagulant therapy, abnormally low ratios of protein S or C to other vitamin K-dependent factors were presented by one patient for protein S and five for protein C. Thus, heterozygous Type I protein S deficiency appeared in seven of 141 patients (5%) and heterozygous Type I protein C deficiency in six of 141 patients (4%). Eleven of thirteen deficient patients had recurrent venous thrombosis. In this group of 141 patients, 1% had an identifiable fibrinogen abnormality, 2% a plasminogen abnormality, and 3% an antithrombin III deficiency. Thus, among the known plasma protein deficiencies associated with venous thrombosis, protein S and protein C. deficiencies (9%) emerge as the leading identifiable associated abnormalities.

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.

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