A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria

Background. Familial renal glucosuria (FRG) is an isolated disorder of proximal tubular glucose transport, characterized by abnormal urinary glucose excretion in the presence of normal blood glucose levels. Generalized aminoaciduria has not generally been considered a feature of this disorder. FRG has recently been shown to result from mutations in SLC5A2, encoding the kidney-specific low-affinity/high-capacity Na+/glucose cotransporter, SGLT2. The purpose of this study was to examine the phenotypic and genetic characteristics of three unrelated consanguineous families with FRG accompanied by aminoaciduria. Methods. Six children with autosomal-recessive FRG and 12 unaffected family members were evaluated at the clinical and molecular levels. DNA sequence analysis of the entire coding sequence of SLC5A2 was performed in all affected individuals. Haplotype analysis using four polymorphic markers flanking SLC5A2 was performed in all study participants. Results. All affected children were asymptomatic, but displayed massive glucosuria (83 to 169 g/1.73m(2)/day) accompanied by generalized aminoaciduria. Sequence analysis in all patients revealed a novel homozygous missense mutation in exon 8 of SLC5A2, resulting in a lysine to arginine substitution at position 321 of SGLT2 amino acid sequence (K321R). The mutation was confirmed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and was found to completely cosegregate with the FRG phenotype. Haplotype analysis is consistent with identity by descent for the mutation. The K321 residue, presumed to be located in the eighth transmembrane domain of SGLT2, is highly conserved across SGLT homologues. Conclusion. Our findings confirm that mutations in SLC5A2 result in autosomal-recessive FRG. The severe glucosuria in homozygotes for the K321R mutation highlights the importance of the eighth SGLT2 transmembrane domain for normal glucose transport. We suggest that the generalized aminoaciduria accompanying FRG is a consequence of the severe impairment in glucose reabsorption, and is probably not directly related to the SGLT2 mutation. The exact role of the aberrant glucose transport in the pathogenesis of aminoaciduria remains to be established.