Abstract Number: PB0158
Meeting: ISTH 2020 Congress
Background: Inherited Protein S deficiency (PSD) (MIM176880) is a rare automosal dominant disorder caused by rare mutations, mainly in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism (VT).
Aims: We report the study of an extended French pedigree originated from Bordeaux area, South West of France, in which 7 relatives were affected with PSD with free Protein levels ranging between 18% and 38%, and in who no candidate deleterious PROS1 mutation was detected by the direct deep sequencing of the 15 PROS1 exons and of their flanking intronic regions. Of note, 6 of the 7 PSD patients had experienced VT events.
Methods: To identify the molecular defect underlying this familial PSD, we performed whole genome sequencing in 5 PSD patients and 2 unaffected relatives whose main finding was validated by Sanger sequencing. RT-qPCR and Western blot analyses were conducted using different molecular constructs to investigate the impact of the identified PSD causing mutation on the expression and translation of PROS1 in HeLa cells.
Results: We identified a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. . This substitution ACG->ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated that the variant generates a novel overlapping ORF and inhibits the translation of the wild type protein from the main ORF.
Conclusions: This work describes the first example of 5’UTR PROS1 mutation causing PSD through the creation of an upstream ORF, a mutation that is not predicted to be deleterious by standard annotation software. This work further illustrates the importance of exploring regulatory regions when searching for a molecular diagnostics of PSD and other Mendelian disorders.
To cite this abstract in AMA style:Jaspard-Vinassa B, Proust C, Soukarieh O, Mouton C, Huguelin Y, Roux M, Constans J, Boland A, Olaso R, Deleuze J-, Morange P-, Labrouche-Colomer S, Trégouët D-, GENMED Consortium . A Novel Rare C. – 39C>T Mutation in the PROS1 5’UTR Causes Protein S Deficiency by Creating a New Upstream Translation Initiation Codon and an Overlapping Open Reading frame [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/a-novel-rare-c-39ct-mutation-in-the-pros1-5utr-causes-protein-s-deficiency-by-creating-a-new-upstream-translation-initiation-codon-and-an-overlapping-open-reading-frame/. Accessed March 3, 2021.
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