Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5'UTRs

Alexandra Filatova; Ivan Reveguk; Maria Piatkova; Daria Bessonova; Olga Kuziakova; Victoria Demakova; Alexander Romanishin; Veniamin Fishman; Yerzhan Imanmalik; Nikolay Chekanov; Rostislav Skitchenko; Yury Barbitoff; Olga Kardymon; Mikhail Skoblov

doi:10.1093/nar/gkac1247

Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5'UTRs

Nucleic Acids Res. 2023 Feb 22;51(3):1229-1244. doi: 10.1093/nar/gkac1247.

Authors

Alexandra Filatova¹, Ivan Reveguk², Maria Piatkova^{3

4}, Daria Bessonova⁵, Olga Kuziakova⁶, Victoria Demakova⁵, Alexander Romanishin^{6

7}, Veniamin Fishman^{8

9}, Yerzhan Imanmalik⁸, Nikolay Chekanov⁸, Rostislav Skitchenko¹⁰, Yury Barbitoff^{11

12

13}, Olga Kardymon⁸, Mikhail Skoblov¹

Affiliations

¹ Research Centre for Medical Genetics, Moscow, Russia.
² Laboratoire de Biologie Structurale de la Cellule, École Polytechnique, Paris, France.
³ Institute of Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Vladivostok, Russia.
⁴ Institute of high technologies and advanced materials, Far Eastern Federal University, Vladivostok, Russia.
⁵ Medical Center, Far Eastern Federal University, Vladivostok, Russia.
⁶ Institute of Life Sciences and Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
⁷ Institute of Life Sciences, Immanuel Kant Baltic Federal University, Kaliningrad, Russia.
⁸ Artificial Intelligence Research Institute, Moscow, Russia.
⁹ Molecular Mechanisms of Ontogenesis, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
¹⁰ Computer Technologies Laboratory, ITMO University, Saint Petersburg, Russia.
¹¹ Bioinformatics Institute, St. Petersburg, Russia.
¹² Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynaecology, and Reproductology, St. Petersburg, Russia.
¹³ Dpt. of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg, Russia.

Abstract

An increasing number of studies emphasize the role of non-coding variants in the development of hereditary diseases. However, the interpretation of such variants in clinical genetic testing still remains a critical challenge due to poor knowledge of their pathogenicity mechanisms. It was previously shown that variants in 5'-untranslated regions (5'UTRs) can lead to hereditary diseases due to disruption of upstream open reading frames (uORFs). Here, we performed a manual annotation of upstream translation initiation sites (TISs) in human disease-associated genes from the OMIM database and revealed ∼4.7 thousand of TISs related to uORFs. We compared our TISs with the previous studies and provided a list of 'high confidence' uORFs. Using a luciferase assay, we experimentally validated the translation of uORFs in the ETFDH, PAX9, MAST1, HTT, TTN,GLI2 and COL2A1 genes, as well as existence of N-terminal CDS extension in the ZIC2 gene. Besides, we created a tool to annotate the effects of genetic variants located in uORFs. We revealed the variants from the HGMD and ClinVar databases that disrupt uORFs and thereby could lead to Mendelian disorders. We also showed that the distribution of uORFs-affecting variants differs between pathogenic and population variants. Finally, drawing on manually curated data, we developed a machine-learning algorithm that allows us to predict the TISs in other human genes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5' Untranslated Regions*
Databases, Genetic*
Disease* / genetics
Humans
Open Reading Frames*
Protein Biosynthesis

Substances

5' Untranslated Regions