Abstract
Familial renal glucosuria (FRG) is characterized by persistent glucosuria despite normal serum glucose and in the absence of overt tubular dysfunction. Mutation of sodium/glucose co-transporter 2 (SGLT2) has been identified and was recently reported to be involved in FRG. However, the functional and pathological consequences of such mutations remain unknown. In the current study, we collected four families with FRG. Sequencing of the SGLT2 coding region, intronic segments and cDNA revealed three missense mutations (294C>A: F98L; 1388T>G: L463R; 1435C>G: R479G) and two splice mutations (IVS 1-16 C>A: Del exon3; IVS 11 + 1 G>C: Del exon11). The probands were either heterozygous or compound heterozygous for SGLT2 mutations, and had glucosuria quantified at 6–27 g/day. Human 293 cells were transfected with the plasmid constructs to study the expression and function of SGLT2 mutants in vitro. Confocal microscopy using green fluorescent protein (GFP) revealed that the mutation results in a loss of punctate membrane pattern typical of the wild-type SGLT2 except in the 294C>A mutant. All mutants had significantly lower transport capacity in comparison to the wild-type control (26.49–71.48%). Renal biopsy in one consenting proband revealed significantly lower SGLT2 expression in the apical side of the proximal convoluted tubule in comparison to both healthy and disease controls (minimal change disease and diabetic nephropathy). The current study provides functional clues regarding the SGLT2 molecule from genotype to phenotype in FRG families.
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Acknowledgments
We thank the FRG patient and healthy controls who participated in this study. This work was funded by the National Natural Science Foundation of China (#30825021 and 30971371), Specialized Research Fund for the Doctoral Program of Higher Education of China (#200800010086), and the Foundation of Ministry of Health of China (#200802052).
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Yu, L., Lv, JC., Zhou, Xj. et al. Abnormal expression and dysfunction of novel SGLT2 mutations identified in familial renal glucosuria patients. Hum Genet 129, 335–344 (2011). https://doi.org/10.1007/s00439-010-0927-z
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DOI: https://doi.org/10.1007/s00439-010-0927-z