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

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.

The First Potentially Causal Genetic Variant Documented in a Polish Woman with Multiple Cavernous Malformations of the Brain

“…The NM_007217.4 ( PDCD10 ): c.395+1G>A (rs1559952220) variant localizes within the canonical splice donor site following exon 6, specifically its first nucleotide ( G T). Mutations destroying canonical splice sites prevent normal splicing, which can lead to the formation of transcripts including introns, partial deletions, or fully skipped exons, with or without the introduction of a premature termination codon (PTC), which yields truncated or otherwise non-functional protein [ 19 , 20 , 21 ]. Interestingly, the NM_007217.4 ( PDCD10 ): c.395+2T>G (rs1559952217) variant is localized within the very same canonical donor site, in its second nucleotide (G T ).…”

Thrombotic Disorders and Antithrombotic Treatments Special Issue

“…Yet, because ACS and IS are multifactorial diseases, in the last few decades, the association of atherothrombosis to other predisposing conditions as a genetic predisposition was frequently looked for, and inherited thrombophilia was often investigated in this setting without univocal results [2]. So, because the association between inherited thrombophilia and atherothrombosis is still matter of discussion, other genetic alterations that tend to be associated with thrombotic diseases are also under investigation [3]. On the other hand, the association between inherited thrombophilia and thrombotic events is better studied for venous thromboembolism (VTE), and in this setting, the association between gene and environmental causes is well known.…”