The kidneys play a critical role in maintaining glucose homeostasis. Under normal renal tubular function, most of the glucose filtered from the glomeruli is reabsorbed in the proximal tubules, leaving only trace amounts in the urine. Glycosuria can occur as a symptom of generalized proximal tubular dysfunction or when the reabsorption threshold is exceeded or the glucose threshold is reduced, as seen in familial renal glycosuria (FRG). FRG is characterized by persistent glycosuria despite normal blood glucose levels and tubular function and is primarily associated with mutations in the sodium/glucose cotransporter 5A2 gene, which encodes the sodium-glucose cotransporter (SGLT) 2. Inhibiting SGLTs has been proposed as a novel treatment strategy for diabetes, and since FRG is often considered an asymptomatic and benign condition, it has inspired preclinical and clinical studies using SGLT2 inhibitors in type 2 diabetes. However, patients with FRG may exhibit clinical features such as lower body weight or height, altered systemic blood pressure, diaper dermatitis, aminoaciduria, decreased serum uric acid levels, and hypercalciuria. Further research is needed to fully understand the pathophysiology, molecular genetics, and clinical manifestations of renal glucosuria.

• Sodium-glucose cotransporters
• Basolateral glucose transporters
• Familial renal glucosuria
• Intestinal glucose-galactose malabsorption
• Fanconi-Bickel syndrome
• Sodium-glucose cotransporter 2 inhibitors

• Female
• Humans
• Glycosuria, Renal/genetics
• East Asian People
• Mutation
• Mutation, Missense
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/genetics
• Sodium-Glucose Transporter 2/genetics

• rare variants
• paediatric kidney disease
• genetic predisposition to disease
• disease genetics
• urinary tract infection

• SCL5A2 gene
• SGLT2 protein
• renal glycosuria

• SGLT2
• familial renal glucosuria
• gene mutation
• genetic kidney disease
• whole exome sequencing

• Child, Preschool
• Failure to Thrive/etiology
• Failure to Thrive/genetics
• Female
• Glycated Hemoglobin/analysis
• Glycosuria/etiology
• Glycosuria/genetics
• Heterozygote
• Humans
• Hypoglycemia/etiology
• Hypoglycemia/genetics
• Sodium-Glucose Transporter 2/genetics

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.

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.

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.

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.

• SLC5A2 gene
• exon skipping
• exonic variant
• minigene analysis
• missense variant
• pre-mRNA splicing