Clinical Manifestation and Mutation Spectrum of 53 Unrelated Pedigrees with Protein S Deficiency in China

Abstract

Protein S (PS) deficiency is associated with a 10-fold increased risk of venous thromboembolism (VTE), but its diagnosis is quite difficult and complicated. In this study, we identified 53 unrelated pedigrees with PS deficiency in China. Data of their clinical characteristics and laboratory examinations were collected. Genetic analysis of PROS1 including direct sequencing, copy number variant detection and messenger ribonucleic acid analysis was performed in probands and related family members. Of these 53 probands, 52.8% (28/53) experienced multi-site and/or recurrent thrombotic episodes, mainly manifested as deep venous thrombosis and/or pulmonary embolism (82.7%). Additional risk factors of VTE were observed in 39.6% (21/53) probands who exhibited a significantly higher rate of recurrent VTE compared with those not, in which 7 probands were complicated by anti-phospholipid syndrome. Most probands and family members exhibited quantitative PS deficiency with impairment of both activated protein C and tissue factor pathway inhibitor cofactor activities. Note that 87.2% (34/39) PROS1 detectable mutation rate was obtained through comprehensive phenotypic and genetic analysis. A total of 36 PROS1 causative mutations including 16 novel mutations were identified in 48 probands, whereas no PROS1 mutations were detected in the other 5 probands. Three hotspot mutations (Glu67Ala, Arg561Trp and Tyr560*) were identified in the Chinese population for the first time. This article provides a framework for correlating the clinical pathogenesis of PS deficiency to genetic backgrounds in the Chinese population.

Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S

“…Homozygous or compound heterozygous PS deficiency is extremely rare, usually presenting with massive VTE or purpura fulminans neonatally 1 25. In the recent 20 years, several reports of compound heterozygosity with later onset of VTE were also available in the literature 22 26–29. The probands in these studies remained free of thrombosis until they became teenagers and suffered from recurrent thrombosis after that, which was the same as the propositus reported in our own study.…”

“…In a young Chinese man who suffered from recurrent venous thrombosis with very low level of PS activity, we have identified compound heterozygous mutations, one novel small indel mutation and one missense mutation in PROS1 gene, the latter of which was reported before by other study groups,21 22 but the pathological mechanism remained unknown. In the current study, the relationship between the genotype and phenotype detection was analysed by thrombin generation test (TGT), and the pathological mechanisms of these two mutations causing PS deficiency were further investigated by recombinant PS expression experiments in vitro.…”

“…Depending on the phenotype, it was reported that approximately half of the PS-deficient subjects became symptomatic at the age of 55, whereas others remained unaffected,24 30 as reflected in the propositus’ parents. The potential mechanism is still unclear, and part of it may be explained by concomitant thrombophilic defects and exposure to transient risk factor for VTE,31 such as surgery, trauma, immobilisation, air travel, pregnancy/puerperium or systemic hormonal contraception or replacement therapy,24 as patients with heterozygous p.R561W mutation, who carried the same mutation as the asymptomatic father, had a much higher risk of recurrent VTE when they combined with hyperhomocysteinaemia or they were pregnant 22. Besides, the thrombosis risk in inherited PS deficiency also depends on PS level.…”

Changes in Biomarkers of Coagulation, Fibrinolytic, and Endothelial Functions for Evaluating the Predisposition to Venous Thromboembolism in Patients With Hereditary Thrombophilia

“…But the incidence bias may be existed because the majority of patients were referred to our center by local clinicians for screening the thrombotic risk factors after the diagnosis of first or recurrent VTE. 27 Ultimately, we chose 17 AT-deficient, 39 PC-deficient, 38 PS-deficient, and 6 combined anticoagulant-deficient patients from our center to constitute the thrombophilia group. It is worth noting that these values only represented the composition of the 3 defects in this group rather than the incidences in the population.…”

A novel rare c. -39C>T mutation in thePROS15’UTR causing PS deficiency by creating a new upstream translation initiation codon and inhibiting the production of the natural protein

“…Some intronic splice variants (Choi et al , 2011; Menezes et al , 2017; Wang et al , 2019) and structural variants (Hurtado et al , 2009; Lind-Halldén et al , 2012; Seo et al , 2014) have also been reported. Note that, compared to exonic variations, very few variations have been described in the promoter region of the PROS1 gene (Espinosa-Parrilla et al , 2000; Hurtado et al , 2008; Li et al , 2019; Sanda et al , 2007; Tang et al , 2013) and even fewer have been functionally characterized. To our knowledge, the c.-168C>T is the sole PROS1 promoter variation that has been experimentally demonstrated to cause inherited PSD by affecting the core binding site of Sp1 transcription factor (Sanda et al , 2007).…”