Abstract
BackgroundFamilial 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.MethodsWe 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.ResultsOur 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.ConclusionTo 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.
Highlights
Familial renal glucosuria (FRG) is a rare renal tubular disease, which is characterized by persistent glucosuria without aberrant glucose metabolism and any other symptoms of tubular malfunction (Calado et al, 2008; Aires et al, 2015; Wang et al, 2019)
We selected the variants within two bases of 5 or 3 ends of the exons, or these variants were predicted to have an effect on splicing regulatory elements according to Human Splicing Finder version 3.1 (HSF) (The total number of disrupted ESEs and gained ESSs is more than 5)
9 missense variants [c.216C > A p.(Phe72Leu), c.294C > A p.(Phe98Leu), c.305C > T p.(Ala102Val), c.599C > A p.(Thr200Lys), c.655G > A p.(Ala219Thr), c.886G > C p.(Val296Leu), c.932A > G p.(Lys311Arg), c.962A > G p.(Lys321Arg) and c.1129G > A p.(Gly377Ser)] located in five exons of the SLC5A2 gene were included in this study (Table 1 and Figure 1A)
Summary
Familial renal glucosuria (FRG) is a rare renal tubular disease, which is characterized by persistent glucosuria without aberrant glucose metabolism and any other symptoms of tubular malfunction (Calado et al, 2008; Aires et al, 2015; Wang et al, 2019). The vast majority of FRG patients are associated with SLC5A2 (OMIM 182381) pathogenic variants Most mutation analyses are performed mainly at genome level, and the impact of a variant on the encoded mRNA and protein is only predicted from the DNA sequence (López-Bigas et al, 2005). 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
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