Genotype and Laboratory and Clinical Phenotypes of Protein S Deficiency

Duebgen, Sebastian; Kauke, Teresa; Marschall, Christoph; Giebl, Andreas; Lison, Susanne; Hart, Christina; Dick, Andrea; Spannagl, Michael

doi:10.1309/ajcp40uxnbtxgkux

Cited by 28 publications

(29 citation statements)

References 28 publications

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“…Vitamin K-dependent Protein S (PROS1, MIM#: 176880) is a cofactor of the anticoagulant enzyme activated protein C (APC), a protease which cleaves procoagulant Factors Va and VIIIa (Garcia de Frutos and Fuentes-Prior 2007). Damaging mutations in Protein S cause hereditary VTE in populations of European descent, with a fivefold higher relative risk in familial carriers (Gandrille et al 2000;Makris et al 2000;Duebgen et al 2012;Holzhauer et al 2012). Recent research recommends genetic screening in cases of hereditary thrombophilia caused by PROTEIN C (MIM#: 612283), PROTEIN S, or ANTITHROMBIN III (MIM#: 107300) mutations because of a significantly increased risk of VTE in carriers versus noncarriers (Holzhauer et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Population‐specific single‐nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans

Daneshjou

Cavallari

Weeke

et al. 2016

Mol Genet Genomic Med

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IntroductionAfrican Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population‐specific genetic factors influencing the higher VTE rate are not well characterized.MethodsWe performed a candidate gene analysis on an exome‐sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP).ResultsIn the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case–control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51–15.20; allele frequencies – cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26–4.10).ConclusionsWe found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case–control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population‐specific genetic risk factor for VTE in African Americans.

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Section: Introductionmentioning

confidence: 99%

Population‐specific single‐nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans

Daneshjou

Cavallari

Weeke

et al. 2016

Mol Genet Genomic Med

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“…Familial and case-control studies suggest that PSD is associated with a 2.5-to 11-fold increased risk of venous thrombosis [15,19,20]. In addition to congenital deficiency, there are a number of physiologic and pathologic conditions that lead to decreased plasma ProS levels such as oral contraceptives, pregnancy, hormone-replacement therapy, and hepatic disorders [21,22]. PSD has been traditionally classified into three types: Type I (quantitative deficiency with reduced total and free ProS antigen levels and reduced anticoagulant activity), Type II (qualitative deficiency with normal total and free ProS antigen levels but low anticoagulant activity), and Type III (normal total ProS antigen levels, low free ProS antigen levels, and low anticoagulant activity).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of protein S deficiency in China

et al. 2013

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Protein S (ProS) is a physiological inhibitor of coagulation with an important function in the downregulation of thrombin generation. ProS deficiency is a major risk factor for venous thrombosis. This study enrolled 40 ProS-deficient probands to investigate the molecular basis of hereditary ProS deficiency in Chinese patients. A mutation analysis was performed by resequencing the PROS1 gene. Large deletions were identified by multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 20 different mutations, including 15 novel mutations, were identified in 21 of the 40 index probands. Small mutations were detected in 18 (45.0%) probands, and large deletions were found in 3 (7.5%) probands, leaving 19 (47.5%) patients without causative variants. To evaluate the functional consequences of 2 novel missense variants, ex vivo thrombin-generation assays, bioinformatics tools, and in vitro expression studies were employed. The p.Asn365Lys ProS variant was found to have moderately impaired secretion and reduced activated protein C cofactor activity. In contrast, the p.Pro410His mutant appeared to have severely impaired secretion but full anticoagulant activity. This study is the largest investigation of ProS deficiency in China and the first investigation of the influence of Type I ProS missense mutations on the global level of coagulation function. The p.K196E mutation, which is common in the neighboring Japanese population, was not found in our Chinese population, and null mutations were common in our Chinese population but not common in Japan. Further genetic analysis is warranted to understand the causes of ProS deficiency in patients without a genetic explanation. Am. J.

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“…The underlying risk factors for increased thrombophilia activity of our patient were relatively lower plasma concentrations of proteins C and S. Patients with protein C levels less than 50% are likely to have a true hereditary deficiency, whereas levels between 55% and 65% such as in our patient may reflect heterozygous deficiency or the low end of the normal distribution [6]. Patients with protein S deficiency generally have activity levels less than 60% of normal activity [7]. Our patient with mild deficiency of proteins C ad S might not be detectably associated with a risk of thrombosis, but which could be provoked by dual severe dengue fever and influenza infection.…”

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confidence: 62%

Acute Pulmonary Embolism in Dual Dengue Fever and Influenza B Infection

Hsu¹

2017

Int J Virol AIDS

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Genotype and Laboratory and Clinical Phenotypes of Protein S Deficiency

Cited by 28 publications

References 28 publications

Population‐specific single‐nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans

Population‐specific single‐nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans

Molecular basis of protein S deficiency in China

Acute Pulmonary Embolism in Dual Dengue Fever and Influenza B Infection

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