Genetic and Phenotypic Variability between Families with Hereditary Protein S Deficiency

2002 ◽  
Vol 87 (02) ◽  
pp. 258-265 ◽  
Author(s):  
David Lane ◽  
Bengt Zöller ◽  
Blandine Mille-Baker ◽  
Mike Laffan ◽  
Björn Dahlbäck ◽  
...  
Keyword(s):  
Mixed Type ◽  
Stop Codon ◽  
Phenotypic Variability ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Wild Type ◽  
Intracellular Degradation ◽  
Metabolic Labelling ◽  
S Deficiency

SummaryWhile many mutations thought to result in protein S (PS) deficiency are known, there have been few attempts to relate genotype expression with plasma phenotype. We have investigated the nature and consequence of PS gene (PROS1) mutations in 17 PS-deficient families who presented with mixed type I and type III phenotypes. Seven different mutations were found in nine families: delG-34 (STOP codon at –24), Val-24Glu, Arg49Cys, Asn217Ser, Gly295Val, +5 G to A intron j and His623Pro. PS wild type (PSWT) and the five missense mutants were transiently expressed in COS-1 cells. All mutants expressed lower (p<0.05) PS antigen compared to PSWT (100%). The mutants Val-24Glu, Gly295Val and His623Pro expressed very low/undetectable PS levels. The mutant Asn217Ser produced around 30% of PSWT, while the mutant Arg49Cys had the highest PS levels (around 50%). Metabolic labelling and pulse-chase experiments showed that all of the mutants had impaired secretion, but this was of variable severity. Also, enhanced intracellular degradation of unsecreted material was found for all mutants. There was a strong correspondence between plasma free PS levels in carriers of the mutations, secreted PS from transfected COS-1 cells and labelled PS from 24 h conditioned medium in pulse-chase experiment. We conclude that the magnitude of secretion defect depends on the nature of the PROS1 mutation and influences the level of free PS in plasma. It is likely that the severity of the secretion defect will determine the risk for venous thrombosis.

scholarly journals Protein S deficiency type I: identification of point mutations in 9 of 10 families

Blood ◽  
1995 ◽  
Vol 86 (9) ◽  
pp. 3444-3451 ◽  
Author(s):  
S Mustafa ◽  
I Pabinger ◽  
C Mannhalter
Keyword(s):  
Stop Codon ◽  
Direct Sequencing ◽  
Protein S ◽  
Type I ◽  
Missense Mutations ◽  
Protein S Deficiency ◽  
Site Mutation ◽  
Frame Shift ◽  
S Deficiency ◽  
Deficiency Type

We identified potentially causative mutations in the active protein S gene (PROS 1) by direct sequencing of PROS 1-specific polymerase chain reaction (PRC) products of all 15 exons, including exon-intron boundaries in 10 families with hereditary protein S deficiency type I. Seven different mutations were found in 9 of 10 families, including one frame shift mutation, a previously published splice site mutation (both occurring in two unrelated families), four missense mutations, and a stop codon at the beginning of exon 12. In family studies, cosegregation of the mutation with the disease could be demonstrated for five mutations; for two missense mutations, this was not possible due to limited family data. All seven mutations were the only abnormalities identified in the respective index patients and were absent in 44 to 62 normal individuals. Therefore, they most likely represent the causal gene defects. For five mutations, analysis of ectopic RNA could be performed. Mutant transcripts were present in the case of the frame shift and three of the missense mutations, while no mutant RNA could be detected in the case of the stop codon.

scholarly journals Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency

Haematologica ◽  
2010 ◽  
Vol 95 (9) ◽  
pp. 1563-1571 ◽  
Author(s):  
E. Castoldi ◽  
L. F. A. Maurissen ◽  
D. Tormene ◽  
L. Spiezia ◽  
S. Gavasso ◽  
...  
Keyword(s):  
Mixed Type ◽  
Protein S ◽  
Hypercoagulable State ◽  
Type I ◽  
Protein S Deficiency ◽  
Type Iii ◽  
S Deficiency ◽  
Thrombosis Risk

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.

A Mutation in the Protein S Pseudogene Is Linked to Protein S Deficiency in a Thrombophilic Family

1989 ◽  
Vol 62 (03) ◽  
pp. 897-901 ◽  
Author(s):  
Hans K Ploos van Amstel ◽  
Pieter H Reitsma ◽  
Karly Hamulyák ◽  
Christine E M de Die-Smulders ◽  
Pier M Mannucci ◽  
...  
Keyword(s):  
Total Protein ◽  
Protein S ◽  
Southern Analysis ◽  
Type I ◽  
Protein S Deficiency ◽  
S Deficiency ◽  
The Family ◽  
Dna Pattern ◽  
Deficiency Type ◽  
S Genes

SummaryProbands from 15 unrelated families with hereditary protein S deficiency type I, that is having a plasma total protein S concentration fifty percent of normal, were screened for abnormalities in their protein S genes by Southern analysis. Two probands were found to have a deviating DNA pattern with the restriction enzyme Mspl. In the two patients the alteration concerned the disappearance of a Mspl restriction site, CCGG, giving rise to an additional hybridizing Mspl fragment.Analysis of relatives of both probands showed that in one family the mutation does not co-segregate with the phenotype of reduced plasma protein S. In the family of the other proband, however, complete linkage between the mutated gene pattern and the reduced total protein S concentration was found: 12 heterozygous relatives showed the additional Mspl fragment but none of the investigated 26 normal members of the family. The mutation is shown to reside in the PSβ gene, the inactive protein S gene. The cause of type I protein S deficiency, a defect PSα gene has escaped detection by Southern analysis. No recombination has occurred between the PSα gene and the PSβ gene in 23 informative meioses. This suggests that the two protein S genes, located near the centromere of chromosome 3, are within 4 centiMorgan of each other.

Protein S mRNA in Patients with Protein S Deficiency

1995 ◽  
Vol 73 (05) ◽  
pp. 746-749 ◽  
Author(s):  
E Sacchi ◽  
M Pinotti ◽  
G Marchetti ◽  
G Merati ◽  
L Tagliabue ◽  
...  
Keyword(s):  
Gene Polymorphism ◽  
Total Protein ◽  
Restriction Analysis ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Phenotypic Analysis ◽  
S Deficiency ◽  
Deficiency Type ◽  
S Genes

SummaryA protein S gene polymorphism, detectable by restriction analysis (BstXI) of amplified exonic sequences (exon 15), was studied in seven Italian families with protein S deficiency. In the 17 individuals heterozygous for the polymorphism the study was extended to platelet mRNA through reverse transcription, amplification and densitometric analysis. mRNA produced by the putative defective protein S genes was absent in three families and reduced to a different extent (as expressed by altered allelic ratios) in four families. The allelic ratios helped to distinguish total protein S deficiency (type I) from free protein S deficiency (type IIa) in families with equivocal phenotypes. This study indicates that the study of platelet mRNA, in association with phenotypic analysis based upon protein S assays in plasma, helps to classify patients with protein S deficiency.

Possible Role for Increased C4b-Binding-Protein Level in Acquired Protein S Deficiency in Type I Diabetes

Diabetes ◽  
1990 ◽  
Vol 39 (4) ◽  
pp. 447-449 ◽  
Author(s):  
A. Ceriello ◽  
D. Giugliano ◽  
A. Quatraro ◽  
E. Marchi ◽  
M. Barbanti ◽  
...  
Keyword(s):  
Protein Level ◽  
Type I Diabetes ◽  
Binding Protein ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
S Deficiency

scholarly journals Identification of Two Novel Point Mutations in the Human Protein S Gene Associated With Familial Protein S Deficiency and Thrombosis

1996 ◽  
Vol 16 (12) ◽  
pp. 1407-1415 ◽  
Author(s):  
Muyao Li ◽  
George L. Long
Keyword(s):  
Genomic Dna ◽  
Mrna Level ◽  
Point Mutations ◽  
Protein S ◽  
Type I ◽  
Protein S Deficiency ◽  
Cdna Sequencing ◽  
Thrombotic Disease ◽  
S Gene ◽  
S Deficiency

Individuals with thrombosis who were believed to possess associated familial protein S deficiency were analyzed for mutations in the protein S gene by a two-step process. First, the individuals were analyzed for protein S Pro 626 A/G dimorphism in both their genomic DNA and reverse-transcribed (RT) polymerase chain reaction (PCR)–amplified cDNA from peripheral blood cell mRNA. If a heterozygote expressed both alleles at the mRNA level at this site in genomic DNA, a search for point mutations was made by direct cDNA sequencing. RT-PCR amplification of exons 1-6 with mRNA from two twin sisters, each of whom has severe type I protein S deficiency, revealed both larger and smaller fragments in addition to the expected 504–base pair fragment in normal individuals. A donor splice-site mutation at position +4 of the 5′ end of intron A was subsequently identified in both sisters and their mother. This mutation would lead to incorrect precursor mRNA splicing and the observed cDNA products. Translation of the altered mRNAs would result in a truncated protein without biological activity. In a second family, cDNA sequencing revealed a T→G mutation at codon 603 (Ile→Ser) in exon 15 of the protein S gene in an individual with protein S deficiency (mixed type) and a history of thrombosis. The same mutation was also detected in the proband's mother and grandmother, both of whom also exhibit protein S deficiency and thrombotic disease. This mutation occurs within a disulfide loop of protein S that is believed to be responsible for binding to C4b binding protein and may result in greater affinity between protein S and C4b, consequently leading to thrombotic disease.

scholarly journals 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

2006 ◽  
Vol 81 (10) ◽  
pp. 787-797 ◽  
Author(s):  
Kazuhiro Mizukami ◽  
Toru Nakabayashi ◽  
Sumiyoshi Naitoh ◽  
Mika Takeda ◽  
Takashi Tarumi ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Deep Vein Thrombosis ◽  
Protein S ◽  
Recurrent Mutation ◽  
Type I ◽  
Protein S Deficiency ◽  
Vein Thrombosis ◽  
S Deficiency ◽  
Deep Vein

FAMILIAL TYPE I PROTEIN S DEFICIENCY ASSOCIATED WITH SEVERE VENOUS THROMBOSIS. A STUDY OF FIVE CASES

1987 ◽  
Author(s):  
C Boyer-Neumann ◽  
M Wolf ◽  
J Amiral ◽  
A M Guyager ◽  
D Meyer ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Plasma Protein ◽  
Active Form ◽  
Vena Cava ◽  
Protein S ◽  
Immunological Methods ◽  
Type I ◽  
Protein S Deficiency ◽  
Free Protein ◽  
S Deficiency

Protein S deficiency has been demonstrated in 5 members from the same family with a history of severe recurrent venous thrombosis over three generations. The propositus, a 16 year old female, had a first spontaneous thrombotic episode at age 15. Phlebography revealed a total obstruction of her left ilio-femoral vein with an extension to the vena cava. She was treated with heparin followed by oral anticoagulant therapy. The four other affected members (mother, aunts and uncle of the propositus) had also presented recurrent thrombosis with onset at a young age. The grandfather, not tested, had died from massive pulmonary embolism at age 54. The immunological assay of protein S was performed in plasma by Laurell, using a monospecific antiserum to human protein S, or by an ELISA, using a kit from Diagnostica Stago (Asserachrom Protein S). In order to separate free protein S, the functionally active form, from protein S complexed with C4-binding protein, plasma was adsorbed with 3.75 % polyethyleneglycol (PEG 6000). Following PEG precipitation, the levels of free protein S antigen remaining in the supernatant were quantitated by the usual immunological methods. In addition, two-dimensional immunoelectrophoresis (DDIE) also provided information on the distribution of both forms. In plasma protein S levels were decreased (40 to 55 % of the normal range) in two untreated patients and lower levels (17 to 20 96) were observed in the three others, including the propositus, who were under dicoumarol therapy. In PEG treated-plasma, protein S was undetectable (less than 5 %) in all patients, indicating a lack of free protein S. This was confirmed by DDIE : whereas protein S migrated as two distinct peaks, corresponding to free and complexed protein S in normal plasma, only a single peak of complexed protein S was observed in all affected patients. These results clearly demonstrate a total lack of free protein S which appears to be responsible for the thromboembolic disorder in this family as there was no deficiency of the other plasma inhibitors (antithrombin III, heparin cofactor II and protein C). According to the classification recently proposed by Comp et al., this family belongs to type I protein S deficiency, with an autosomal dominant mode of inheritance.

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