A novel mutation Gly222Arg in <i>PROS1</i> causing protein S deficiency in a patient with pulmonary embolism

Xu, Jiaqi; Peng, Gehong; Ouyang, Yao

doi:10.1002/jcla.23111

Cited by 3 publications

(6 citation statements)

References 9 publications

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“…Studies have reported that genetic changes in PROS1 have a negative effect on the functionality of PS. Around 360 genetic mutations linked to PS deficiency have been recorded in the mutation database so far (20,21). The 4 missense mutations detected in our study are in PROS1 (p.K296Q, p.A307H, p.R316H, p.A303V).…”

Section: Discussionmentioning

confidence: 61%

Pathogenic Ala303Val mutation in the PROS1 gene is associated with the pathogenesis of Deep Vein Thrombosis

Akın¹

2021

Erciyes Med J

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Section: Discussionmentioning

confidence: 61%

Pathogenic Ala303Val mutation in the PROS1 gene is associated with the pathogenesis of Deep Vein Thrombosis

Akın¹

2021

Erciyes Med J

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“…Mutations in PROS1 lead to decreased PS levels and activity in patients and lead to PSD, which reduces the ability of auxiliary APC to inactivate FVa and FVIIa, resulting in thrombosis. For example, a missense PROS1 mutation (Gly222Arg) has been identi ed in a patient with pulmonary embolism, which causes PS activity to decrease to 5.0% [22].The PS activity of several codon mutations near L607, such as Ser627fs, Ser627 ins101fsX34 (acc HGMD nomenclature), p.Ala536Val, p.Asn583His, p.Thr617Ile, p.Asp624His, and p.Cys666Ser (acc HGVS nomenclature) are all less than 40%, and the lowest is 12%, suggesting that mutation of the corresponding domain causes serious functional defects [23]. The diagnosis of hereditary PSD is generally based on clinical manifestations, plasma PS levels, activity detection, and gene detection [24].…”

Section: Discussionmentioning

confidence: 99%

A Thrombophilia Family With Protein S Deficiency Due to Protein Translation Disorders Caused By a Leu607Ser Heterozygous Mutation in PROS1

Zhang

Lin

et al. 2021

Preprint

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Background: Protein S deficiency (PSD) is an autosomal dominant hereditary disease. In 1984, familial PSD was reported to be prone to recurrent thrombosis. Follow-up studies have shown that heterozygous protein S (PROS1) mutations increase the risk of thrombosis. More than 300 PROS1 mutations have been identified; among them, only a small number of mutations have been reported its possible mechanism to reduce plasma protein S (PS) levels. However, whether PROS1 mutations affect protein structure and why it can induce PSD remains unknown.Methods: The clinical phenotypes of the members of a family with thrombosis were collected. Their PS activity was measured using the coagulation method, whereas their protein C and antithrombin III activities were measured using methods such as the chromogenic substrate method. The proband and her parents were screened for the responsible mutation using second-generation whole exon sequencing, and the members of the family were verified for suspected mutations using Sanger sequencing. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to detect the mRNA and protein expression of PROS1.Results: In this family, the proband with venous thrombosis of both lower extremities, the proband’s mother with pulmonary thrombosis and venous thrombosis of both lower extremities, and the proband’s younger brother had significantly lower PS activity and carried a PROS1 c. 1820T > C:p.Leu607Ser heterozygous mutation (NM_000313.3). However, no such mutations were found in family members with normal PS activity. The PS expression in the cell lysate and supernatant of the Leu607Ser mutant cells decreased, while mRNA expression increased. Immunofluorescence localization showed that there was no significant difference in protein localization before and after mutation.Conclusions: The analysis of family phenotype, gene association, and cell function tests suggest that the PROS Leu607Ser heterozygous mutation may be a pathogenic mutation. Serine substitution causes structural instability of the entire protein. These data indicate that impaired PS translation and synthesis or possible secretion impairment is the main pathogenesis of this family with hereditary PSD and thrombophilia.

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“…The molecular genetic analysis of a 23-year-old patient who experienced venous thrombosis showed a homozygous missense mutation, G664>A, in exon7 of PROS1 [52]. This mutation results in the replacement of glycine by arginine at codon 222, and the mutation causes a reduction in PS level [52]. This alteration was the first reported mutation of PS codon 222 [52].…”

Section: Mutations Of Protein Smentioning

confidence: 92%

“…This mutation results in the replacement of glycine by arginine at codon 222, and the mutation causes a reduction in PS level [52]. This alteration was the first reported mutation of PS codon 222 [52]. Hereditary PS deficiency caused by a mutation/deletion in PROS1 is autosomal dominant, which means that an individual who inherits only one mutant PROS1 gene nevertheless has an increased chance of developing symptoms of PS deficiency.…”

Section: Mutations Of Protein Smentioning

confidence: 99%

“…We selected these mutations because they are unique and have been observed only recently. The molecular genetic analysis of a 23-year-old patient who experienced venous thrombosis showed a homozygous missense mutation, G664>A, in exon7 of PROS1 [52]. This mutation results in the replacement of glycine by arginine at codon 222, and the mutation causes a reduction in PS level [52].…”

Section: Regulation Of Protein Smentioning

confidence: 99%

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Protein S: function, regulation, and clinical perspectives

Majumder

Nguyen

2021

Current Opinion in Hematology

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Purpose of review Protein S (PS) is an essential natural anticoagulant. PS deficiency is a major contributor to acquired hypercoagulability. Acquired hypercoagulability causes myocardial infarction, stroke, and deep vein thrombosis in millions of individuals. Yet, despite its importance in hemostasis, PS is the least understood anticoagulant. Even after 40 years since PS was first described, we are still uncovering information about how PS functions. The purpose of this review is to highlight recent findings that advance our understanding of the functions of PS and explain hypercoagulability caused by severe PS deficiency. Recent findings PS has long been described as a cofactor for Activated Protein C (APC) and Tissue Factor Pathway Inhibitor (TFPI). However, a recent report describes direct inhibition of Factor IXa (FIXa) by PS, an activity of PS that had been completely overlooked. Thrombophilia is becoming a more frequently reported disorder. Hereditary PS deficiency is an anticoagulant deficiency that results eventually in thrombophilia. In addition, PS deficiency is a predisposing factor for venous thromboembolism (VTE), but an effect of PS deficiency in arterial thrombosis, such as arterial ischemic stroke, is uncertain. Plasma PS concentration decreases in pregnant women. Inherited thrombophilias are important etiologies for recurrent pregnancy loss, and anticoagulation therapy is of benefit to women with recurrent pregnancy loss who had documented only PS deficiency. Hypoxia is a risk factor for VTE, and hypoxia downregulates plasma PS level. Importantly, COVID-19 can lead to hypoxemia because of lung damage from IL6-driven inflammatory responses to the viral infection. Because hypoxia decreases the abundance of the key anticoagulant PS, we surmise that the IL6-induced cytokine explosion combined with hypoxemia causes a drop in PS level that exacerbates the thrombotic risk in COVID-19 patients. Summary This review is intended to advance understanding of the anticoagulant function of an important plasma protein, PS. Despite 40+ years of research, we have not had a complete description of PS biology as it pertains to control of blood coagulation. However, the picture of PS function has become sharper with the recent discovery of FIXa inhibition by PS. Hemostasis mediated by PS now includes regulation of FIXa activity alongside the cofactor activities of PS in the TFPI/APC pathways. In addition, the direct inhibition of FIXa by PS suggests that PS, particularly a small derivative of PS, could be used to treat individuals with PS deficiencies or abnormalities that cause thrombotic complications.

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A novel mutation Gly222Arg in PROS1 causing protein S deficiency in a patient with pulmonary embolism

Cited by 3 publications

References 9 publications

Pathogenic Ala303Val mutation in the PROS1 gene is associated with the pathogenesis of Deep Vein Thrombosis

Pathogenic Ala303Val mutation in the PROS1 gene is associated with the pathogenesis of Deep Vein Thrombosis

A Thrombophilia Family With Protein S Deficiency Due to Protein Translation Disorders Caused By a Leu607Ser Heterozygous Mutation in PROS1

Protein S: function, regulation, and clinical perspectives

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