Non-canonical regulation of Endoglin by rare and common variants: new molecular and clinical perspectives for Hereditary Hemorrhagic Telangiectasia and beyond

Abstract

AbstractEndoglin, encoded by theENGgene, is a transmembrane glycoprotein with a major implication in angiogenesis. Loss-of functionENGvariants are responsible for Hereditary Hemorrhagic Telangiectasia (HHT), a rare vascular disease, characterized with a large inter-individual clinical heterogeneity. But, Endoglin and its soluble form have also been reported to be involved in other pathologic conditions including cancer and thrombosis. Thus, dissecting the genetic regulation of Endoglin holds the potential to deepen our understanding of the pathophysiology underlying HHT and other human diseases. To follow-up our latest study in which we characterized 5 rare HHT-causing variations in the 5’UTR of ENG, all creating overlapping upstream Open Reading Frames (upORFs) initiated with upstream AUG, we here performed an exhaustivein silicoanalysis of all possible single nucleotide variants (n=328) predicted to create or modify any type of upORF in the 5’UTR of ENG. We demonstrated that 85% (11/13) of variants creating uAUGs in frame with the same stop codon located at position c.125, decrease the Endoglin levelsin vitro.We identified the moderate effect on ENG of a rare uCUG-creating variant found in HHT patients. Our obtained experimental results were in partial correlation with bioinformatics predictions based on Kozak sequence and PreTIS scores.In parallel, we leveraged results from large scale plasma proteogenomics resources and identified 8 loci (ABO, ASGR1, B3GNT8, ENG, HBS1L, NCOA6, PLAUR,andTIRAP), presenting common polymorphisms, significantly associated with Endoglin levels. The ABO locus, coding for the ABO blood groups, explain ∼5% of the inter-individual variability of ENG plasma levels. Overall, these loci candidates could contribute to explain the incomplete penetrance of known pathogenic mutations and/or the clinical heterogeneity of HHT patients. Of note, 4 of these loci are also associated with venous thrombosis in the latest INVENT Genome Wide Association Study initiative.This project brings new insights on the interpretation ofENGnon-coding variants and on molecular mechanisms participating to the regulation of Endoglin. It also exemplifies how the incorporation of genotype data on common polymorphisms could enhance the management of rare diseases.