Standard thrombophilia screening revealed a Type I PSD ( Figure 1 Supplementary Table S1). The studied family was ascertained through a proband addressed to the Specialized Clinical Hematology Laboratory of the Pellegrin Hospital (Bordeaux) for a thrombophilia screening in the context of an objectively documented first VT episode early in life (20 years old). 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 and no PSD causing mutation has yet been described in the 5′UTR region of PROS1. Note that, compared with exonic variations, very few variations have been described in the promoter region or the 5′UTR of the PROS1 gene and even fewer have been functionally characterized. Some intronic splice variants and structural variants have also been reported. The majority of identified PSD causing PROS1 mutations are located in the coding regions of the gene or in their flanking sequences and are mainly missense or nonsense single nucleotide variations. However, a substantial proportion of PSD cases remain without any definitive molecular diagnosis, up to 40% according to a recent estimate. Previous works have shown that complete or partial PSD was associated with increased risk of venous thrombosis (VT). Īutosomal dominant inherited PS deficiency (PSD) (MIM 612336) is a rare disorder caused by private or rare mutations in the structural PROS1 gene. Type I and Type III PS deficiencies account for ∼95% of PS deficiencies and are considered to be the heterogeneous clinical expression of the same molecular defect. This led to the definition of three clinical subtypes of PS deficiencies: (i) Type I refers to deficiency of both free and total PS and decreased PS activity, (ii) Type II is defined by normal plasma levels but decreased PS activity, while (iii) Type III shows decreased free PS plasma levels and decreased PS activity but normal total PS (TPS) plasma levels. Generally, PS plasma concentration can be characterized by antigen measurements of the free and total PS levels or by PS activity. In human plasma, PS circulates both under a free and active form (∼40%) and an inactive form (∼60%) when complexed with C4b-binding protein. PS is a vitamin K-dependent glycoprotein that acts as a cofactor for PC to inactivate factors Va (FVa) and VIIIa (FVIIIa) and to limit thrombin generation via direct interactions with factor Xa (FXa) and FVa. Protein S (PS), with Protein C (PC) and antithrombin (AT), one of the three main natural inhibitors of the coagulation cascade plays a key role in the control of blood clot formation. This work describes the first example of 5′UTR PROS1 mutation causing PSD through the creation of an uORF, a mutation that is not predicted to be deleterious by standard annotation softwares, and emphasizes the need for better exploration of such type of non-coding variations in clinical genomics. We experimentally demonstrated in HeLa cells that the variant generates a novel overlapping upstream open reading frame (uORF) and inhibits the translation of the wild-type PS. This substitution ACG→ATG creates a new start codon upstream of the main ATG. This led to the identification of 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. To identify the molecular defect underlying PSD observed in an extended French pedigree with seven PSD affected members in whom no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via an multiplex ligation-dependent probe amplification (MLPA) approach, a whole genome sequencing strategy was adopted. Set the annotation's direction to 1 for forward arrows and -1 for reverse arrows.Autosomal dominant inherited Protein S deficiency (PSD) (MIM 612336) is a rare disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. names are rendered on top of the annotations. Each Annotation requires 0-based start (inclusive) and end (exclusive) indexes. annotations (=)Īn array of Annotations to render. Shown at the center of the circular viewer. both_flip is the opposite: the linear viewer is on the left, and the circular viewer is on the right. both means the circular viewer fills the left side of SeqViz, and the linear viewer fills the right. One of "linear" | "circular" | "both" | "both_flip". The type and orientation of the sequence viewers. Import seqparse from "seqparse" export default ( ) => Optional viewer (='both')
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