SLC5A2 – Familial Renal Glucosuria

Familial renal glucosuria (FRG) is a rare renal tubular disorder characterised by isolated glucosuria despite normal serum glucose levels, occurring without other proximal tubule dysfunction. Recessive loss-of-function variants in the SLC5A2 gene, encoding the sodium–glucose co-transporter 2 (SGLT2), underlie familial renal glucosuria by impairing renal glucose reabsorption at the S1 segment of the proximal convoluted tubule.

Initial case series described a homozygous nonsense mutation and novel compound heterozygous SLC5A2 variants (e.g., c.500del (p.Gln167fsTer) and c.1961A>G (p.Asn654Ser)) in affected individuals, confirming autosomal recessive inheritance (PMID:14614622).

A multisite cohort of 23 Korean children uncovered 21 distinct SLC5A2 mutations, including missense, frameshift, splice, and nonsense alleles, with compound heterozygosity or homozygosity in severe cases and heterozygotes showing milder glucosuria (PMID:22314875).

Segregation was demonstrated by cosegregation of SLC5A2 variants with FRG in multiple families (e.g., six affected individuals in three consanguineous pedigrees with homozygous K321R) and haplotype analysis supporting identity by descent (PMID:15610225).

Functional assays in HEK293 and Xenopus oocyte systems revealed that missense variants (e.g., p.Phe98Leu, p.Arg479Gly) and splice-site changes lead to reduced SGLT2 membrane expression and transport capacity (26–71% of wild-type), confirming a loss-of-function mechanism (PMID:21165652; PMID:27000029).

Collectively, strong genetic evidence from >50 unrelated probands, segregation data, and moderate functional concordance support a definitive gene–disease link. Clinical testing of SLC5A2 variants guides diagnosis of FRG, informs carrier screening, and shapes assessment of SGLT2 inhibitor pharmacogenetics. Key Take-home: Loss-of-function mutations in SLC5A2 cause autosomal recessive familial renal glucosuria with a codominant phenotype spectrum.

References

• Human genetics • 2004 • Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. PMID:14614622
• Kidney international • 2005 • A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria. PMID:15610225
• Pediatric nephrology (Berlin, Germany) • 2012 • Familial renal glucosuria: a clinicogenetic study of 23 additional cases. PMID:22314875
• Human genetics • 2011 • Abnormal expression and dysfunction of novel SGLT2 mutations identified in familial renal glucosuria patients. PMID:21165652
• BMC nephrology • 2016 • Decreased expression and function of sodium-glucose co-transporter 2 from a novel C-terminal mutation: a case report. PMID:27000029

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