Molecular Analysis of the SGLT2 Gene in Patients with Renal Glucosuria

Abstract

Abstract. The role of SGLT2 (the gene for a renal sodiumdependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutations were detected. Most of them were private; only a splice mutation was found in 5 families of different ethnic backgrounds, and a 12-bp deletion was found in two German families. Fourteen individuals (including the original patient with 'renal glucosuria type 0') were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.

Familial Renal Glucosuria and SGLT2

“…Analysis of the genomic structure of human SGLT2 revealed a 14-exon gene that spans 8 kb with an intron-exon organization that is similar to SGLT1 (44). All of the introns display the donor and acceptor splice consensus sequences GT/AG, and a previously unreported CA repeat was identified in intron 1.…”

“…In particular, other SGLTs that are known to be expressed in the kidney and whose functions have not yet been clarified are candidates for modifier genes in FRG. At least three patients have been reported not to have any mutation identified after sequencing of the entire coding region of SLC5A2 (44,45), which also raises the possibility of genetic heterogeneity. Indeed, a locus on chromosome 6, in close genetic linkage with the HLA complex, has been positioned and named GLYS1 on the basis of segregation analysis in five unrelated affected pedigrees (52); however, this hypothetical gene remains to be cloned.…”

“…Among them are missense and nonsense mutations, small deletions (in-frame and frame shift), and splicing mutations. IVS7 ϩ 5G may be considered a mutational hot spot because of the recurrent finding of the IVS7 ϩ 5G3 A allele in several unrelated families who have FRG and are of different ethnic origin (44,46). Molecular analysis may also be helpful in understanding the findings of earlier titration studies.…”

“…Molecular analysis may also be helpful in understanding the findings of earlier titration studies. Haploinsufficiency will result in a reduced number of normally functioning carriers in the renal tubule, thereby leading to type A glucosuria, whereas certain missense mutations might decrease SGLT2 affinity for glucose and patients will display type B glucosuria (44). Compound heterozygosity for SGLT2 mutations, however, is probably the reason that many past cases of severe glucosuria could Figure 4.…”

The Na+/glucose cotransporters: from genes to therapy

“…Individuals are homozygous or compound heterozygous for an SGLT2 mutation. Approximately 21 different gene mutations have been described for SGLT2, leading to persistent renal glycosuria, with glucose excretion of up to 160 g/day (52). At the higher level of excretion, there is a complete absence of glucose reabsorption from the glomerular filtrate (52,53).…”