Novel Splice Site Mutation in the PROS1 Gene in a Polish Patient with Venous Thromboembolism: c.602-2delA, Splice Acceptor Site of Exon 7.

Magdalena Mrożek,Ewa Wypasek,Daniel P Potaczek,Anetta Undas,Martine Alhenc-Gelas

doi:10.3390/medicina56090485

Abstract

We identified a novel splice site mutation of the PROS1 gene in a Polish family with protein S (PS) deficiency and explored the molecular pathogenesis of this previously undescribed variant. A novel mutation was detected in a 26-year-old woman with a history of venous thromboembolism (VTE) provoked by oral contraceptives. Her family history of VTE was positive. The sequence analysis of the PROS1 gene was performed in the proband and the proband’s family. The proband and their asymptomatic father had lower free PS levels (45% and 50%, respectively) and PS activity (48% and 44%, respectively). Total PS levels were normal (65.6% and 62.4%, respectively). The sequence analysis of the PROS1 gene revealed the presence of heterozygous deletion at the nucleotide position c.602-2 in intron 6, just upstream of exon 7, detected in the proband and her father. This variant alters the splice acceptor site of exon 7, and, according to the in silico prediction, it is highly likely to cause in-frame exon 7 skipping. We also presented follow-up data of two other Polish patients with PS deficiency associated with splice site mutations in PROS1 gene.

Highlights

Protein S (PS) is a vitamin K-dependent glycoprotein that serves as a cofactor of activated proteinC (PC) in the proteolysis of activated factor (F) V and FVIII [1]
The current report presents a novel splice site c.602-2delA mutation detected in a Polish family with PS deficiency, together with a long-term follow-up of two other cases with venous thromboembolism (VTE) associated with splice site mutations in the PROS1 gene, treated in our Centre for Coagulation Disorders
Exon skipping has been reported as the most common alternative splicing event, which due to loss of functional domains/sites or shifting of the open reading frame may lead to synthesis of the shortened but still functional protein, despite the genetic mutation [10]

Summary

Introduction

Protein S (PS) is a vitamin K-dependent glycoprotein that serves as a cofactor of activated protein. C (PC) in the proteolysis of activated factor (F) V and FVIII [1]. PS was identified as a cofactor of tissue factor pathway inhibitor (TFPI) which stimulates the inhibition of FXa by TFPI [2]. Until now there have been about 360 genetic mutations associated with PS deficiency (HGMD database, http://www.hgmd.org). As few as 44 splice site mutations have been reported (HGMD database, http://www.hgmd.org) among PS-deficient subjects to date, including two PROS1 gene mutations observed in Polish patients with VTE, i.e., c.1155+5G>A and c.965+4A>G [7]. The current report presents a novel splice site c.602-2delA mutation detected in a Polish family with PS deficiency, together with a long-term follow-up of two other cases with VTE associated with splice site mutations in the PROS1 gene, treated in our Centre for Coagulation Disorders

Patients

Laboratory Measurements

Genetic Testing

Results

Discussion