Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency

Espinosa‐Parrilla, Yolanda; Morell, Marta; Souto, Joan Carles; Tirado, Isabel; Fontcuberta, Jordi; Estivill, Xavier; Sala, Núria

doi:10.1002/(sici)1098-1004(1999)14:1<30::aid-humu4>3.0.co;2-x

Cited by 31 publications

(23 citation statements)

References 30 publications

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“…Similarly, the absence of mutated mRNA from c.258,259AG>GT indicates that what causes PS deficiency is not the p.V87F substitution that would result from this mutation if normally spliced, but an alteration of the normal splicing of intron 3. This agrees with the observation that this mutation reduces the consensus value of the wild type donor splice site of intron 3 to a value lower than the one calculated for the c.259G>C (p.V87L) mutation, 7 which also results in reduced mRNA expression. 18 Since it was confirmed that [c.-7C>G;44T>A] and p.M640T are not affected by nonsense-mediated mRNA decay, their functional consequences, as well as those of c.1272delA and p.R233K, were analyzed by means of transient transfection experiments in COS-7 cells.…”

Section: Discussionsupporting

confidence: 91%

“…7,32 All patients gave their informed consent to participation in this study and all procedures were reviewed and approved by the ethics committee for clinical research of the Ciutat Sanitària i Universitària de Bellvitge (CSUB). Here, we have adopted HUGO recommendations for mutation nomenclature (http://www.hgvs.org/mutnomen/).…”

Section: Pros1 Mutations Analyzedmentioning

confidence: 99%

“…7,32 Isolated total RNA from frozen peripheral blood platelets 33 was reverse transcribed by use of random hexamer primers and the First Strand cDNA Synthesis Kit (Amersham Biosciences, Uppsala, Sweden). For each patient, 50 ng of PROS1 cDNA were amplified by polymerase chain reaction (PCR) with primers overlapping two contiguous exons upstream and downstream of the mutation site (available upon request).…”

Section: Pros1 Mrna Studiesmentioning

confidence: 99%

“…6 According to plasma levels of total and free PS antigen and to the functional activity of PS, three types of PS deficiency have been proposed. Type I is a quantitative deficiency characterized by reduced levels of total and free PS antigen, as well as anticoagulant activity; type II is a qualitative deficiency characterized by normal levels of PS antigen but reduced anticoagulant activity; type III PS deficiency, which may be considered as a mild quantitative deficiency, 7 is characterized by normal levels of total PS antigen but reduced levels of free PS antigen and activity. The thrombotic risk associated with heterozygous type I PS deficiency is between 2.5 and 10-fold higher than in the general population.…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency

Hurtado¹,

Muñoz²,

Mulero³

et al. 2008

Haematologica

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Section: Discussionsupporting

confidence: 91%

Section: Pros1 Mutations Analyzedmentioning

confidence: 99%

Section: Pros1 Mrna Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency

Hurtado¹,

Muñoz²,

Mulero³

et al. 2008

Haematologica

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“…In families having the PROS1 mutation, the phenotype more often shows type I rather than type III deficiency. These findings led to the conclusion that type I PS deficiency is a monogenic disease caused by PROS1 mutations, while type III PS deficiency is more complex or heterogeneous disorder (70,71).…”

Section: Protein S Deficiencymentioning

confidence: 99%

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game

Bereczky

Kovács

Muszbek

2010

Clinical Chemistry and Laboratory Medicine

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Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins that play an important role in the regulation of blood coagulation as natural anticoagulants. PC is activated by thrombin and the resulting activated PC (APC) inactivates membrane-bound activated factor VIII and factor V. The free form of PS is an important cofactor of APC. Deficiencies in these proteins lead to an increased risk of venous thromboembolism; a few reports have also associated these deficiencies with arterial diseases. The degree of risk and the prevalence of PC and PS deficiency among patients with thrombosis and in those in the general population have been examined by several population studies with conflicting results, primarily due to methodological variability. The molecular genetic background of PC and PS deficiencies is heterogeneous. Most of the mutations cause type I deficiency (quantitative disorder). Type II deficiency (dysfunctional molecule) is diagnosed in approximately 5%-15% of cases. The diagnosis of PC and PS deficiencies is challenging; functional tests are influenced by several pre-analytical and analytical factors, and the diagnosis using molecular genetics also has special difficulties. Large gene segment deletions often remain undetected by DNA sequencing methods. The presence of the PS pseudogene makes genetic diagnosis even more complicated. Clin Chem Lab Med 2010;48:S53-66.

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Optimization of a simple and rapid single-strand conformation analysis for detection of mutations in thePROS1 gene: Identification of seven novel mutations and three novel, apparently neutral, variants

et al. 2000

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Anticoagulant protein S (PS) deficiency is a known risk factor for thrombophilia. The structure and high allelic heterogeneity of the PS gene (PROS1), together with the presence of a 97% homologous pseudogene, complicates PROS1 analysis. We have optimized a simple, fast, and non‐isotopic Single‐Strand Conformation Analysis (SSCA or SSCP) method for PROS1 mutation detection. This is accomplished through the analysis of the single‐stranded and heteroduplex DNA fragments corresponding to 15 PCR segments that include part of the 5′‐upstream region and the 15 PROS1 exons with their intron boundaries. To standardize the method, 13 known PROS1 mutations or allele variants in 10 different fragments were analyzed under different electrophoretic conditions. The results indicated that, using a combination of two different electrophoretic settings, all the allele variants could be detected as a single‐strand band shift and/or by the presence of a heteroduplex. This method was used to analyze the PROS1 gene in 31 propositi with different types of PS deficiency and thrombosis. Ten different cosegregating mutations, seven of which are novel (143C‐>G, L‐27H, G96X, M599T, P626L, 1418delA, and 1877delT), were identified in the five families suffering from type I or quantitative PS deficiency and in four of the nine families with coexistence of type I and type III phenotypes. No clearly co‐segregating PROS1 mutations were identified in any of the 17 type III propositi analyzed, although eight of them were heterozygotes for the uncommon P460 allele of the S/P460 variant. Furthermore, five apparently neutral allelic variants, three of which are novel (‐296C‐>T, 182G‐>C and T57S), were identified in a normal control, two type I/III and two type III PS‐deficient pedigrees. Hum Mutat 15:463–473, 2000. © 2000 Wiley‐Liss, Inc.

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Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency

Cited by 31 publications

References 30 publications

Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency

Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game

Optimization of a simple and rapid single-strand conformation analysis for detection of mutations in thePROS1 gene: Identification of seven novel mutations and three novel, apparently neutral, variants

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