Novel SLC5A2 Mutations and Genetic Characterization in Korean Patients with Familial Renal Glucosuria
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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.
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.
참고문헌 (24)
- Santer R, "Molecular analysis of the SGLT2 gene in patients with renal glucosuria", J Am Soc Nephrol, 14, pp.2873~2882 (2003)[DOI]
- Van den Heuvel LP, "Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2)", Hum Genet, 111, pp.544~547 (2002)[DOI]
- Santer R, "Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target", Clin J Am Soc Nephrol, 5, pp.133~141 (2010)[DOI]
- Elsas LJ, "Familial renal glycosuria: a genetic reappraisal of hexose transport by kidney and intestine", J Clin Invest, 48, pp.1845~1854 (1969)[DOI]
- Kanai Y, "The human kidney low affinity Na+", glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose, 1994, pp.93, 97~404
- Brown GK, "Glucose transporters: structure, function and consequences of deficiency", J Inherit Metab Dis, 23, pp.237~246 (2000)[DOI]
- Wright EM, "Renal Na(+)-glucose cotransporters", Am J Physiol Renal Physiol, 280, pp.F10~F18 (2001)[DOI]
- Calado J, "Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting", Kidney Int, 69, pp.852~855 (2006)[DOI]
- Calado J, "Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria", Hum Genet, 114, pp.314~316 (2004)[DOI]
- Zhao X, "A recurrent deletion in the SLC5A2 gene including the intron 7 branch site responsible for familial renal glucosuria", Sci Rep, 6, pp.33920~ (2016)[DOI]
- Yu L, "Decreased expression and function of sodium-glucose co-transporter 2 from a novel C-terminal mutation: a case report", BMC Nephrol, 17, pp.31~ (2016)[DOI]
- Yu L, "Novel SLC5A2 variants contribute to renal glucosuria in Chinese families: abnormal expression and dysfunction of variant SLC5A2", Hum Mutat, 36, pp.79~86 (2015)[DOI]
- 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, 6, pp.1532~1534 (2013)[DOI]
- Lee H, "Familial renal glucosuria: a clinicogenetic study of 23 additional cases", Pediatr Nephrol, 27, pp.1091~1095 (2012)[DOI]
- Calado J, "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, 23, pp.3874~3879 (2008)[DOI]
- Magen D, "A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria", Kidney Int, 67, pp.34~41 (2005)[DOI]
- Scholl-Burgi S, "Long-term outcome of renal glucosuria type 0: the original patient and his natural history", Nephrol Dial Transplant, 19, pp.2394~2396 (2004)[DOI]
- Schneider D, "Hypercalciuria in children with renal glycosuria: evidence of dual renal tubular reabsorptive defects", J Pediatr, 121, pp.715~719 (1992)[DOI]
- Aires I, "Hypouricaemia and hyperuricosuria in familial renal glucosuria", Clin Kidney J, 6, pp.523~525 (2013)[DOI]
- Oemar BS, "Complete absence of tubular glucose reabsorption: a new type of renal glucosuria (type 0)", Clin Nephrol, 27, pp.156~160 (1987)
- Chen LH, "Inhibition of the sodium glucose co-transporter-2: its beneficial action and potential combination therapy for type 2 diabetes mellitus", Diabetes Obes Metab, 15, pp.392~402 (2013)[DOI]
- Kalra S, "Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Their Basic and Clinical Pharmacology", Diabetes Ther, 5, pp.355~366 (2014)[DOI]
- Ottosson-Laakso E, "Influence of Familial Renal Glycosuria Due to Mutations in the SLC5A2 Gene on Changes in Glucose Tolerance over Time", PLoS One, 11, pp.e0146114~ (2016)[DOI]
- Yu L, "Novel SLC5A2 mutation contributes to familial renal glucosuria: Abnormal expression in renal tissues", Exp Ther Med, 12, pp.649~652 (2016)[DOI]