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Novel SLC5A2 Mutations and Genetic Characterization in Korean Patients with Familial Renal Glucosuria

  • Lee, Weon Kyung (Department of Pediatrics, Inje University College of Medicine) ;
  • Oh, Seung Hwan (Department of Laboratory Medicine, Inje University College of Medicine) ;
  • Chung, Woo Yeong (Department of Pediatrics, Inje University College of Medicine)
  • Received : 2017.10.17
  • Accepted : 2017.10.23
  • Published : 2018.10.31

Abstract

Purpose: Familial renal glucosuria (FRG, OMIM #233100) is a rare but relatively benign genetic condition characterized by persistent isolated glucosuria with a normal blood glucose level. We report three additional SLC5A2 mutations and examine their phenotypic and genetic characteristics in a Korean FRG cohort. We also reviewed the literature and summarized the genotypes of all Korean patients with FRG. Methods: A genetic analysis was conducted by directly sequencing all 14 exons of the SLC5A2 gene and their flanking regions in six unrelated Korean children with FRG and their family members. Novel non-synonymous single-nucleotide polymorphisms were identified and compared with known mutations that are repeatedly detected in the Korean population. Results: We found two novel mutations [c.274G>A (G92S) and c.1168C>T (L390F)] and one known [c.1382G>A (S461N)] mutation in each family and one recurrent mutation [c.1346G>A (G449D) (rs768392222)] in two pedigrees. The recurrent G449D was predicted to be "possibly damaging," with a score of 0.883 in Polyphen-2, while G92S, L390F, and S461N were predicted to be "probably damaging," with scores of 1.000, 0.999, and 0.996, respectively. Conclusions: Two novel, one previously reported, and one recurrent mutation were identified in six Korean FRG pedigrees as causative mutations of renal glucosuria. Sequence variations in the SLC5A2 gene were frequently detected in children with persistent isolated glucosuria. A long-term follow-up of this FRG cohort is needed to understand how these specific SGLT2 mutations impair kidney function and energy homeostasis.

Keywords

References

  1. Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 2003; 14:2873-82. https://doi.org/10.1097/01.ASN.0000092790.89332.D2
  2. Van den Heuvel LP, Assink K, Willemsen M, Monnens L. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet 2002;111:544-7. https://doi.org/10.1007/s00439-002-0820-5
  3. Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol 2010;5:133-41. https://doi.org/10.2215/CJN.04010609
  4. Elsas LJ, Rosenberg LE. Familial renal glycosuria: a genetic reappraisal of hexose transport by kidney and intestine. J Clin Invest 1969;48:1845-54. https://doi.org/10.1172/JCI106150
  5. Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 1994;93:97-404.
  6. Brown GK. Glucose transporters: structure, function and consequences of deficiency. J Inherit Metab Dis 2000;23:237-46. https://doi.org/10.1023/A:1005632012591
  7. Wright EM. Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol 2001;280:F10-8. https://doi.org/10.1152/ajprenal.2001.280.1.F10
  8. Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J, et al. Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney Int 2006;69:852-5. https://doi.org/10.1038/sj.ki.5000194
  9. Calado J, Soto K, Clemente C, Correia P, Rueff J. Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. Hum Genet 2004;114:314-6. https://doi.org/10.1007/s00439-003-1054-x
  10. Zhao X, Cui L, Lang Y, Liu T, Lu J, Wang C, et al. A recurrent deletion in the SLC5A2 gene including the intron 7 branch site responsible for familial renal glucosuria. Sci Rep 2016;6:33920. https://doi.org/10.1038/srep33920
  11. Yu L, Xu Q, Hou P, Zhang H. Decreased expression and function of sodium-glucose co-transporter 2 from a novel C-terminal mutation: a case report. BMC Nephrol 2016;17:31. https://doi.org/10.1186/s12882-016-0244-4
  12. Yu L, Hou P, Lv JC, Liu GP, Zhang H. Novel SLC5A2 variants contribute to renal glucosuria in Chinese families: abnormal expression and dysfunction of variant SLC5A2. Hum Mutat 2015;36:79-86. https://doi.org/10.1002/humu.22714
  13. Lee YW. Clinical and genetic analysis in a patient with primary renal glucosuria: Identification of a novel mutation in the SLC5A2 gene. Exp Ther Med 2013;6:1532-4. https://doi.org/10.3892/etm.2013.1326
  14. Lee H, Han KH, Park HW, Shin JI, Kim CJ, Namgung MK, et al. Familial renal glucosuria: a clinicogenetic study of 23 additional cases. Pediatr Nephrol 2012;27:1091-5. https://doi.org/10.1007/s00467-012-2109-9
  15. Calado J, Sznajer Y, Metzger D, Rita A, Hogan MC, Kattamis A, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant 2008;23:3874-9. https://doi.org/10.1093/ndt/gfn386
  16. Magen D, Sprecher E, Zelikovic I, Skorecki K. A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria. Kidney Int 2005;67:34-41. https://doi.org/10.1111/j.1523-1755.2005.00053.x
  17. Scholl-Burgi S, Santer R, Ehrich JH. Long-term outcome of renal glucosuria type 0: the original patient and his natural history. Nephrol Dial Transplant 2004;19:2394-6. https://doi.org/10.1093/ndt/gfh366
  18. Schneider D, Gauthier B, Trachtman H. Hypercalciuria in children with renal glycosuria: evidence of dual renal tubular reabsorptive defects. J Pediatr 1992;121:715-9. https://doi.org/10.1016/S0022-3476(05)81898-0
  19. Aires I, Santos AR, Pratas J, Nolasco F, Calado J. Hypouricaemia and hyperuricosuria in familial renal glucosuria. Clin Kidney J 2013;6:523-5. https://doi.org/10.1093/ckj/sft100
  20. Oemar BS, Byrd DJ, Brodel J. Complete absence of tubular glucose reabsorption: a new type of renal glucosuria (type 0). Clin Nephrol 1987;27:156-60.
  21. Chen LH, Leung PS. Inhibition of the sodium glucose co-transporter-2: its beneficial action and potential combination therapy for type 2 diabetes mellitus. Diabetes Obes Metab 2013;15:392-402. https://doi.org/10.1111/dom.12064
  22. Kalra S. Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Their Basic and Clinical Pharmacology. Diabetes Ther 2014;5:355-66. https://doi.org/10.1007/s13300-014-0089-4
  23. Ottosson-Laakso E, Tuomi T, Forsen B, Gullstrom M, Groop PH, Groop L, et al. Influence of Familial Renal Glycosuria Due to Mutations in the SLC5A2 Gene on Changes in Glucose Tolerance over Time. PLoS One 2016;11:e0146114. https://doi.org/10.1371/journal.pone.0146114
  24. Yu L, Hou P, Liu GP, Zhang H. Novel SLC5A2 mutation contributes to familial renal glucosuria: Abnormal expression in renal tissues. Exp Ther Med 2016;12:649-52. https://doi.org/10.3892/etm.2016.3388