Soukarieh, O. | Search bioRxiv

bioRxiv2020

MORFEE: a new tool for detecting and annotating single nucleotide variants creating premature ATG codons from VCF files

SummaryVariants in 5UTR regions that create upstream translation initiation AUG codons are a class of neglected non coding variations. When they associate with a premature stop codon and create upstream open reading frames (uORFs) whose translation competes with that of natural proteins, they can have strong impact on human diseases. We here describe MORFEE, a new bioinformatics tool that detects, annotates and predicts, from a standard VCF file, the creation of uORF by any 5UTR variants on uORF creation. MORFEE was applied to two genomic resources and identified candidate functional variants that could explain statistical association signals observed in the context of Genome Wide Association Studies or could be responsible for rare forms of diseases. In conclusion MORFEE is an easy-to-use tool complementary to existing ones that can help resolving genetic investigations that remained so far unfruitful. Availability and implementationMORFEE is written in R with code and package available at https://github.com/daissi/MORFEE. Contactdavid-alexandre.tregouet@inserm.fr; david-alexandre.tregouet@u-bordeaux.fr

bioinformatics↗

bioRxiv2020

A novel rare c. -39C>T mutation in the PROS1 5'UTR causing PS deficiency by creating a new upstream translation initiation codon and inhibiting the production of the natural protein.

Inherited Protein S deficiency (PSD) (MIM176880) is a rare automosal dominant 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. To identify the molecular defect underlying PSD observed in an extended French pedigree with 7 PSD affected members in who no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via a MLPA approach, a whole genome sequencing strategy was adopted. 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. 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 in HeLa cells. This work describes the first example of 5UTR PROS1 mutation causing PSD through the creation of an upstream ORF, a mutation that is not predicted to be deleterious by standard annotation softwares.

genetics↗