title: Novel SLC5A2 variants contribute to renal glucosuria in Chinese families: abnormal expression and dysfunction of variant SLC5A2.
abstract: Familial renal glucosuria (FRG) is characterized by persistent glucosuria despite normal serum glucose and the absence of overt tubular dysfunction. Variants in solute carrier family 5 (sodium-glucose cotransporter), member 2 (SLC5A2) have been reported in FRG patients. However, the functional and expression-related consequences of such variants have been scarcely investigated. In the current study, we studied five FRG families and identified six missense mutations, including four novel variants (c.1051T>C/.(C351R), c.1400T>C/p.(V467A), c.1420G>C/p.(A474P), c.1691G>A/p.(R564Q); RNA not analyzed) and two variants that had been previously reported (c.294C>A/p.(F98L), c.736C>T/p.(P246S); RNA not analyzed). The probands were either heterozygous or compound heterozygous for SLC5A2 variants and had glucosuria of 5.9%-19.6 g/day. Human 293 cells were transfected with plasmid constructs to study the expression and function of SLC5A2 variants in vitro. Western blotting revealed that the expression levels of SLC5A2-351R-GFP, SLC5A2-467A-GFP, SLC5A2-474P-GFP, and SLC5A2-564Q-GFP were significantly decreased compared with wild-type SLC5A2-GFP (37%-55%). Confocal microscopy revealed that three variants (c.1400T>C, c.1420G>C, c.1691G>A) resulted in a loss of the punctate membrane pattern typical of wild-type SLC5A2. All variants had a significantly lower transport capacity in than the wild-type control. The current study provides a starting point to further investigate the molecular mechanism of SLC5A2 in FRG families and provides functional clues for antidiabetes drugs.
authors.affiliation: Renal Division, Inner Mongolia People's Hospital, Hohhot, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Ping
authors.initials: P
authors.lastname: Hou
authors.forename: Ji-Cheng
authors.initials: JC
authors.lastname: Lv
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000328:Adult; D002681:China; D015536:Down-Regulation; D005260:Female; D006030:Glycosuria, Renal / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2
keywords: SLC5A2; expression; familial renal glucosuria; function