Identification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.

The genetic influence in epilepsy, characterized by unprovoked and recurrent seizures, is through variants in genes critical to brain development and function. We have carried out variant calling in Mesial Temporal Lobe Epilepsy (MTLE) patients by mapping the RNA-Seq data available at SRA, NCBI, USA...

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Autores principales:	Tanusree Chaudhuri, Janaki Chintalapati, Madhusoodan Vijayacharya Hosur
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/534ccc3837b8460db2df3d13229d9d9d
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spelling	oai:doaj.org-article:534ccc3837b8460db2df3d13229d9d9d2021-12-02T20:07:18ZIdentification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.1932-620310.1371/journal.pone.0252475https://doaj.org/article/534ccc3837b8460db2df3d13229d9d9d2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252475https://doaj.org/toc/1932-6203The genetic influence in epilepsy, characterized by unprovoked and recurrent seizures, is through variants in genes critical to brain development and function. We have carried out variant calling in Mesial Temporal Lobe Epilepsy (MTLE) patients by mapping the RNA-Seq data available at SRA, NCBI, USA onto human genome assembly hg-19. We have identified 1,75,641 SNVs in patient samples. These SNVs are distributed over 14700 genes of which 655 are already known to be associated with epilepsy. Large number of variants occur in the 3'-UTR, which is one of the regions involved in the regulation of protein translation through binding of miRNAs and RNA-binding proteins (RBP). We have focused on studying the structure-function relationship of the 3'-UTR SNVs that are common to at-least 10 of the 35 patient samples. For the first time we find SNVs exclusively in the 3'-UTR of FGF12, FAR1, NAPB, SLC1A3, SLC12A6, GRIN2A, CACNB4 and FBXO28 genes. Structural modelling reveals that the variant 3'-UTR segments possess altered secondary and tertiary structures which could affect mRNA stability and binding of RBPs to form proper ribonucleoprotein (RNP) complexes. Secondly, these SNVs have either created or destroyed miRNA-binding sites, and molecular modeling reveals that, where binding sites are created, the additional miRNAs bind strongly to 3'-UTR of only variant mRNAs. These two factors affect protein production thereby creating an imbalance in the amounts of select proteins in the cell. We suggest that in the absence of missense and nonsense variants, protein-activity imbalances associated with MTLE patients can be caused through 3'-UTR variants in relevant genes by the mechanisms mentioned above. 3'-UTR SNV has already been identified as causative variant in the neurological disorder, Tourette syndrome. Inhibition of these miRNA-mRNA bindings could be a novel way of treating drug-resistant MTLE patients. We also suggest that joint occurrence of these SNVs could serve as markers for MTLE. We find, in the present study, SNV-mediated destruction of miRNA binding site in the 3'-UTR of the gene encoding glutamate receptor subunit, and, interestingly, overexpression of one of this receptor subunit is also associated with Febrile Seizures.Tanusree ChaudhuriJanaki ChintalapatiMadhusoodan Vijayacharya HosurPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0252475 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tanusree Chaudhuri Janaki Chintalapati Madhusoodan Vijayacharya Hosur Identification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.
description	The genetic influence in epilepsy, characterized by unprovoked and recurrent seizures, is through variants in genes critical to brain development and function. We have carried out variant calling in Mesial Temporal Lobe Epilepsy (MTLE) patients by mapping the RNA-Seq data available at SRA, NCBI, USA onto human genome assembly hg-19. We have identified 1,75,641 SNVs in patient samples. These SNVs are distributed over 14700 genes of which 655 are already known to be associated with epilepsy. Large number of variants occur in the 3'-UTR, which is one of the regions involved in the regulation of protein translation through binding of miRNAs and RNA-binding proteins (RBP). We have focused on studying the structure-function relationship of the 3'-UTR SNVs that are common to at-least 10 of the 35 patient samples. For the first time we find SNVs exclusively in the 3'-UTR of FGF12, FAR1, NAPB, SLC1A3, SLC12A6, GRIN2A, CACNB4 and FBXO28 genes. Structural modelling reveals that the variant 3'-UTR segments possess altered secondary and tertiary structures which could affect mRNA stability and binding of RBPs to form proper ribonucleoprotein (RNP) complexes. Secondly, these SNVs have either created or destroyed miRNA-binding sites, and molecular modeling reveals that, where binding sites are created, the additional miRNAs bind strongly to 3'-UTR of only variant mRNAs. These two factors affect protein production thereby creating an imbalance in the amounts of select proteins in the cell. We suggest that in the absence of missense and nonsense variants, protein-activity imbalances associated with MTLE patients can be caused through 3'-UTR variants in relevant genes by the mechanisms mentioned above. 3'-UTR SNV has already been identified as causative variant in the neurological disorder, Tourette syndrome. Inhibition of these miRNA-mRNA bindings could be a novel way of treating drug-resistant MTLE patients. We also suggest that joint occurrence of these SNVs could serve as markers for MTLE. We find, in the present study, SNV-mediated destruction of miRNA binding site in the 3'-UTR of the gene encoding glutamate receptor subunit, and, interestingly, overexpression of one of this receptor subunit is also associated with Febrile Seizures.
format	article
author	Tanusree Chaudhuri Janaki Chintalapati Madhusoodan Vijayacharya Hosur
author_facet	Tanusree Chaudhuri Janaki Chintalapati Madhusoodan Vijayacharya Hosur
author_sort	Tanusree Chaudhuri
title	Identification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.
title_short	Identification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.
title_full	Identification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.
title_fullStr	Identification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.
title_full_unstemmed	Identification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.
title_sort	identification of 3'-utr single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/534ccc3837b8460db2df3d13229d9d9d
work_keys_str_mv	AT tanusreechaudhuri identificationof3utrsinglenucleotidevariantsandpredictionofselectproteinimbalanceinmesialtemporallobeepilepsypatients AT janakichintalapati identificationof3utrsinglenucleotidevariantsandpredictionofselectproteinimbalanceinmesialtemporallobeepilepsypatients AT madhusoodanvijayacharyahosur identificationof3utrsinglenucleotidevariantsandpredictionofselectproteinimbalanceinmesialtemporallobeepilepsypatients
_version_	1718375302252462080

Identification of 3'-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients.

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