Common and Rare 5′UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics

Soukarieh, Omar; Meguerditchian, Caroline; Proust, Carole; Aïssi, Dylan; Eyries, Mélanie; Goyenvalle, Aurélie; Trégouët, David‐Alexandre

doi:10.3389/fcvm.2022.841032

Cited by 14 publications

(9 citation statements)

References 78 publications

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“…These variants modify important motifs in the region leading to an altered binding of regulatory proteins to the gene elements [ 62 ]. Further, these variants either pre-dispose an individual to a disease or reduces the disease risk [ 3 , 63 ]. Therefore, it is important to understand the disease mechanism at genetic level as well as protein level.…”

Section: Discussionmentioning

confidence: 99%

PRKCE non-coding variants influence on transcription as well as translation of its gene

et al. 2022

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Untranslated regions of the gene play a crucial role in gene expression regulation at mRNA and protein levels. Mutations at UTRs impact expression by altering transcription factor binding, transcriptional/translational efficacy, miRNA-mediated gene regulation, mRNA secondary structure, ribosomal translocation, and stability. PKCε, a serine/threonine kinase, is aberrantly expressed in numerous diseases such as cardiovascular disorders, neurological disorders, and cancers; its probable cause is unknown. Therefore, in the current study, the influence of PRKCE 5’-and 3'UTR variants was explored for their potential impact on its transcription and translation through several bioinformatics approaches. UTR variants data was obtained through different databases and initially evaluated for their regulatory function. Variants with regulatory function were then studied for their effect on PRKCE binding with transcription factors (TF) and miRNAs, as well as their impact on mRNA secondary structure. Study outcomes indicated the regulatory function of 73 5'UTR and 17 3'UTR variants out of 376. 5'UTR variants introduced AP1 binding sites and promoted the PRKCE transcription. Four 3'UTR variants introduced a circular secondary structure, increasing PRKCE translational efficacy. A region in 5'UTR position 45,651,564 to 45,651,644 was found where variants readily influenced the miRNA-PRKCE mRNA binding. The study further highlighted a PKCε-regulated feedback loop mechanism that induces the activity of TFs, promoting its gene transcription. The study provides foundations for experimentation to understand these variants’ role in diseases. These variants can also serve as the genetic markers for different diseases’ diagnoses after validation at the cell and population levels.

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Section: Discussionmentioning

confidence: 99%

PRKCE non-coding variants influence on transcription as well as translation of its gene

et al. 2022

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“…We in silico mutated each position in the 5'UTR of the main transcript of ENG (MANE select, ENST00000373203.9) reported in the latest version of Ensembl database (GRCh38.p14) with the 3 alternative nucleotides to generate a vcf file containing all possible single nucleotide variations (SNVs) between positions c.-303 (i.e., first nucleotide of the 5'UTR) and c.-1 (Supplementary Table 1). The generated vcf file was then annotated using an updated version of the MORFEE bioinformatics tool 26,42 now available on https://github.com/CarolineMeg/MORFEE. Compared to its initial version that abled to annotate variants creating upstream AUGs or deleting upstream stop codons, the current version can annotate variations predicted to (i) create canonical and non-canonical TIS; (ii) create new stop codons (TAA, TAG and TGA); and/or (iii) delete existing stop codons along a given transcript.…”

Section: In Silico Mutational Saturation Of the 5'utr Of Eng And Sear...mentioning

confidence: 99%

Unveiling Endoglin non canonical regulation: spotlight on the new role of the uPAR pathway

Munsch,

Proust,

Deiber

et al. 2024

Preprint

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Endoglin, encoded by the ENG gene, is a transmembrane glycoprotein with a major implication in angiogenesis. Loss-of function ENG variants 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 5UTR of ENG, all creating overlapping upstream Open Reading Frames (upORFs) initiated with upstream AUG, we here performed an exhaustive in silico analysis of all possible single nucleotide variants (n=328) predicted to create or modify any type of upORF in the 5UTR 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 levels in 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, and TIRAP), 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 of ENG non-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.

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“…They also regulate downstream translation through elements including upstream open reading frames (ORFs), internal ribosome entry sites (IRES), m7G cap, polyadenylation signals, microRNA binding sites and secondary structures ( 26 , 30 , 39 , 44 ). With WGS and the advancement of global RNA structure probing in vivo ( 46 ), an increasing number of UTR variants have been discovered and studied for their association with diseases ( 32 , 63 , 80 ) ( Table 2 ). In addition, several UTR variants appear to increase the risk for disease because of differential microRNA binding affinity to altered alleles and subsequent changes in gene expression regulation ( 47 , 66 ).…”

Section: Cardiomyopathy-associated Genetic Variants In Untranslated R...mentioning

confidence: 99%

The role of noncoding genetic variants in cardiomyopathy

Htet,

Lei,

Bajpayi

et al. 2023

Front. Cardiovasc. Med.

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Cardiomyopathies remain one of the leading causes of morbidity and mortality worldwide. Environmental risk factors and genetic predisposition account for most cardiomyopathy cases. As with all complex diseases, there are significant challenges in the interpretation of the molecular mechanisms underlying cardiomyopathy-associated genetic variants. Given the technical improvements and reduced costs of DNA sequence technologies, an increasing number of patients are now undergoing genetic testing, resulting in a continuously expanding list of novel mutations. However, many patients carry noncoding genetic variants, and although emerging evidence supports their contribution to cardiac disease, their role in cardiomyopathies remains largely understudied. In this review, we summarize published studies reporting on the association of different types of noncoding variants with various types of cardiomyopathies. We focus on variants within transcriptional enhancers, promoters, intronic sites, and untranslated regions that are likely associated with cardiac disease. Given the broad nature of this topic, we provide an overview of studies that are relatively recent and have sufficient evidence to support a significant degree of causality. We believe that more research with additional validation of noncoding genetic variants will provide further mechanistic insights on the development of cardiac disease, and noncoding variants will be increasingly incorporated in future genetic screening tests.

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Common and Rare 5′UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics

Cited by 14 publications

References 78 publications

PRKCE non-coding variants influence on transcription as well as translation of its gene

PRKCE non-coding variants influence on transcription as well as translation of its gene

Unveiling Endoglin non canonical regulation: spotlight on the new role of the uPAR pathway

The role of noncoding genetic variants in cardiomyopathy

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