Cargando…

Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay

BACKGROUND: Familial renal glucosuria is a rare renal tubular disorder caused by SLC5A2 gene variants. Most of them are exonic variants and have been classified as missense variants. However, there is growing evidence that some of these variants can be detrimental by affecting the pre-mRNA splicing...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Sai, Wang, Yixiu, Wang, Jinchao, Liu, Zhiying, Zhang, Ruixiao, Shi, Xiaomeng, Han, Yue, Guo, Wencong, Bottillo, Irene, Shao, Leping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674938/
https://www.ncbi.nlm.nih.gov/pubmed/33250922
http://dx.doi.org/10.3389/fgene.2020.585064
_version_ 1783611615823790080
author Wang, Sai
Wang, Yixiu
Wang, Jinchao
Liu, Zhiying
Zhang, Ruixiao
Shi, Xiaomeng
Han, Yue
Guo, Wencong
Bottillo, Irene
Shao, Leping
author_facet Wang, Sai
Wang, Yixiu
Wang, Jinchao
Liu, Zhiying
Zhang, Ruixiao
Shi, Xiaomeng
Han, Yue
Guo, Wencong
Bottillo, Irene
Shao, Leping
author_sort Wang, Sai
collection PubMed
description BACKGROUND: Familial renal glucosuria is a rare renal tubular disorder caused by SLC5A2 gene variants. Most of them are exonic variants and have been classified as missense variants. However, there is growing evidence that some of these variants can be detrimental by affecting the pre-mRNA splicing process. Therefore, we hypothesize that a certain proportion of SLC5A2 exonic variants can result in disease via interfering with the normal splicing process of the pre-mRNA. METHODS: We used bioinformatics programs to analyze 77 previously described presumed SLC5A2 missense variants and identified candidate variants that may alter the splicing of pre-mRNA through minigene assays. RESULTS: Our study indicated six of 7 candidate variants induced splicing alterations. Variants c.216C > A, c.294C > A, c.886G > C, c.932A > G and c.962A > G may disrupt splicing enhancer motifs and generate splicing silencer sequences resulting in the skipping of exon 3. Variants c.305C > T and c.1129G > A probably disturb splice sites leading to exon skipping. CONCLUSION: To our knowledge, we report, for the first time, SLC5A2 exonic variants that produce alterations in pre-mRNA. Our research reinforces the importance of assessing the consequences for putative point variants at the mRNA level. Additionally, we propose that minigenes function analysis may be valuable to evaluate the impact of SLC5A2 exonic variants on pre-mRNA splicing without patients’ RNA samples.
format Online
Article
Text
id pubmed-7674938
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-76749382020-11-27 Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay Wang, Sai Wang, Yixiu Wang, Jinchao Liu, Zhiying Zhang, Ruixiao Shi, Xiaomeng Han, Yue Guo, Wencong Bottillo, Irene Shao, Leping Front Genet Genetics BACKGROUND: Familial renal glucosuria is a rare renal tubular disorder caused by SLC5A2 gene variants. Most of them are exonic variants and have been classified as missense variants. However, there is growing evidence that some of these variants can be detrimental by affecting the pre-mRNA splicing process. Therefore, we hypothesize that a certain proportion of SLC5A2 exonic variants can result in disease via interfering with the normal splicing process of the pre-mRNA. METHODS: We used bioinformatics programs to analyze 77 previously described presumed SLC5A2 missense variants and identified candidate variants that may alter the splicing of pre-mRNA through minigene assays. RESULTS: Our study indicated six of 7 candidate variants induced splicing alterations. Variants c.216C > A, c.294C > A, c.886G > C, c.932A > G and c.962A > G may disrupt splicing enhancer motifs and generate splicing silencer sequences resulting in the skipping of exon 3. Variants c.305C > T and c.1129G > A probably disturb splice sites leading to exon skipping. CONCLUSION: To our knowledge, we report, for the first time, SLC5A2 exonic variants that produce alterations in pre-mRNA. Our research reinforces the importance of assessing the consequences for putative point variants at the mRNA level. Additionally, we propose that minigenes function analysis may be valuable to evaluate the impact of SLC5A2 exonic variants on pre-mRNA splicing without patients’ RNA samples. Frontiers Media S.A. 2020-11-05 /pmc/articles/PMC7674938/ /pubmed/33250922 http://dx.doi.org/10.3389/fgene.2020.585064 Text en Copyright © 2020 Wang, Wang, Wang, Liu, Zhang, Shi, Han, Guo, Bottillo and Shao. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Wang, Sai
Wang, Yixiu
Wang, Jinchao
Liu, Zhiying
Zhang, Ruixiao
Shi, Xiaomeng
Han, Yue
Guo, Wencong
Bottillo, Irene
Shao, Leping
Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay
title Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay
title_full Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay
title_fullStr Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay
title_full_unstemmed Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay
title_short Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay
title_sort six exonic variants in the slc5a2 gene cause exon skipping in a minigene assay
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674938/
https://www.ncbi.nlm.nih.gov/pubmed/33250922
http://dx.doi.org/10.3389/fgene.2020.585064
work_keys_str_mv AT wangsai sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT wangyixiu sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT wangjinchao sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT liuzhiying sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT zhangruixiao sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT shixiaomeng sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT hanyue sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT guowencong sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT bottilloirene sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay
AT shaoleping sixexonicvariantsintheslc5a2genecauseexonskippinginaminigeneassay