Genotype-phenotype analysis in familial renal glucosuria patients: the crucial role of conserved residues

Abstract Background and Aims Familial renal glucosuria (FRG) is a hereditary disorder caused by mutations in SLC5A2, the gene encoding sodium-glucose cotransporter 2 (SGLT2) in proximal tubule cells. In this study, we aimed to characterize the genotype-phenotype relationship in FRG patients using data from our cohort and literature review. Method We sequenced SLC5A2 in a cohort of 21 FRG patients and measured the renal threshold of glucose (RTG) in 15 patients using urinary glucose excretion in a 4-hour oral glucose tolerance test (OGTT). We built an open-source online calculator to facilitate the calculation of RTG. Besides, we reviewed published literature and obtained information on SLC5A2 variants and 24-hour urinary glucose (24hUG) in FRG patients. Results We identified 27 rare SLC5A2 variants, including 13 novel variants (G484D, R564W, A212S, c.574+1G>C, W649*, S592Cfs*6, Q579*, A89T, Y339*, V39F, G491E, A464E, and G360D), in our cohort and yielded 107 SLC5A2 variants from literature review. RTG in our cohort ranged from 1.0 to 9.2mmol/L. Patients carrying two SLC5A2 variants had lower RTG (3.9 vs. 6.2 mmol/L, p = 0.057) and larger amounts of 24-hour urinary glucose excretion (24hUG) (52.39 vs. 7.20 g/1.73m2, p = 2.7*10−8) than those carrying a single variant. Patients with homozygous missense or in-frame indels had mean 24hUG of 82.30g/1.73m2, comparable to those with homozygous truncating variants (81.66g/1.73m2) and significantly more than those with homozygous splicing variants (35.38g/1.73m2, p = 0.026). Patients with homozygous missense variants involving conservative residues had more 24hUG (104.76g/1.73m2) than those with variants at non-conservative residues (46.37g/1.73m2, p = 0.0031). Conclusion We built a comprehensive map showing the impact of SLC5A2 variant type, variant location, and zygosity on glucosuria severity. Our results highlighted that conserved residues play an essential role in maintaining the transport function of SGLT2.