AUTHOR=Wang Sai , Wang Yixiu , Wang Jinchao , Liu Zhiying , Zhang Ruixiao , Shi Xiaomeng , Han Yue , Guo Wencong , Bottillo Irene , Shao Leping TITLE=Six Exonic Variants in the SLC5A2 Gene Cause Exon Skipping in a Minigene Assay JOURNAL=Frontiers in Genetics VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.585064 DOI=10.3389/fgene.2020.585064 ISSN=1664-8021 ABSTRACT=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.