J Korean Med Sci.  2016 Jan;31(1):47-54. 10.3346/jkms.2016.31.1.47.

Mutations in SLC12A3 and CLCNKB and Their Correlation with Clinical Phenotype in Patients with Gitelman and Gitelman-like Syndrome

• Lee JW
• Lee J
• Heo NJ
• Cheong HI
• Han JS

• KMID: 2359991
• DOI: http://doi.org/10.3346/jkms.2016.31.1.47

Abstract

Gitelman's syndrome (GS) is caused by loss-of-function mutations in SLC12A3 and characterized by hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Long-term prognosis and the role of gene diagnosis in GS are still unclear. To investigate genotype-phenotype correlation in GS and Gitelman-like syndrome, we enrolled 34 patients who showed hypokalemic metabolic alkalosis without secondary causes. Mutation analysis of SLC12A3 and CLCNKB was performed. Thirty-one patients had mutations in SLC12A3, 5 patients in CLCNKB, and 2 patients in both genes. There was no significant difference between male and female in clinical manifestations at the time of presentation, except for early onset of symptoms in males and more profound hypokalemia in females. We identified 10 novel mutations in SLC12A3 and 4 in CLCNKB. Compared with those with CLCNKB mutations, patients with SLC12A3 mutations were characterized by more consistent hypocalciuria and hypomagnesemia. Patients with 2 mutant SLC12A3 alleles, compared with those with 1 mutant allele, did not have more severe clinical and laboratory findings except for lower plasma magnesium concentrations. Male and female patients did not differ in their requirement for electrolyte replacements. Two patients with concomitant SLC12A3 and CLCNKB mutations had early-onset severe symptoms and showed different response to treatment. Hypocalciuria and hypomagnesemia are useful markers in differentiation of GS and classical Bartter's syndrome. Gender, genotypes or the number of SLC12A3 mutant alleles cannot predict the severity of disease or response to treatment.

Keyword

Gitelman Syndrome; Bartter Syndrome; SLC12A3; CLCNKB; Salt-losing Tubulopathy

MeSH Terms

Adolescent
Adult
Alleles
Bartter Syndrome/genetics/pathology
Chloride Channels/*genetics
DNA Mutational Analysis
Female
Genetic Association Studies
Genotype
Gitelman Syndrome/*genetics/pathology
Humans
Hypokalemia/etiology
Male
Middle Aged
Phenotype
Polymorphism, Genetic
Solute Carrier Family 12, Member 3/genetics
Young Adult
Chloride Channels
Solute Carrier Family 12, Member 3

Reference

1. Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet. 1997; 17:171–178.

2. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet. 1996; 13:183–188.

3. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet. 1996; 14:152–156.

4. Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996; 12:24–30.

5. Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB. Yale Gitelman's and Bartter's Syndrome Collaborative Study Group. Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int. 2001; 59:710–717.

6. Lo YF, Nozu K, Iijima K, Morishita T, Huang CC, Yang SS, Sytwu HK, Fang YW, Tseng MH, Lin SH. Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman's syndrome. Clin J Am Soc Nephrol. 2011; 6:630–639.

7. Vargas-Poussou R, Dahan K, Kahila D, Venisse A, Riveira-Munoz E, Debaix H, Grisart B, Bridoux F, Unwin R, Moulin B, et al. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol. 2011; 22:693–703.

8. Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005; 85:423–493.

9. Reissinger A, Ludwig M, Utsch B, Prömse A, Baulmann J, Weisser B, Vetter H, Kramer HJ, Bokemeyer D. Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles. Kidney Blood Press Res. 2002; 25:354–362.

10. Jeck N, Konrad M, Peters M, Weber S, Bonzel KE, Seyberth HW. Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediatr Res. 2000; 48:754–758.

11. Zelikovic I, Szargel R, Hawash A, Labay V, Hatib I, Cohen N, Nakhoul F. A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes. Kidney Int. 2003; 63:24–32.

12. Joo KW, Lee JW, Jang HR, Heo NJ, Jeon US, Oh YK, Lim CS, Na KY, Kim J, Cheong HI, et al. Reduced urinary excretion of thiazide-sensitive Na-Cl cotransporter in Gitelman syndrome: preliminary data. Am J Kidney Dis. 2007; 50:765–773.

13. Nozu K, Fu XJ, Nakanishi K, Yoshikawa N, Kaito H, Kanda K, Krol RP, Miyashita R, Kamitsuji H, Kanda S, et al. Molecular analysis of patients with type III Bartter syndrome: picking up large heterozygous deletions with semiquantitative PCR. Pediatr Res. 2007; 62:364–369.

14. Melander O, Orho-Melander M, Bengtsson K, Lindblad U, Râstam L, Groop L, Hulthén UL. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension. 2000; 36:389–394.

15. Bettinelli A, Bianchetti MG, Girardin E, Caringella A, Cecconi M, Appiani AC, Pavanello L, Gastaldi R, Isimbaldi C, Lama G, et al. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr. 1992; 120:38–43.

16. Berry MR, Robinson C, Karet Frankl FE. Unexpected clinical sequelae of Gitelman syndrome: hypertension in adulthood is common and females have higher potassium requirements. Nephrol Dial Transplant. 2013; 28:1533–1542.

17. Reilly RF, Huang CL. The mechanism of hypocalciuria with NaCl cotransporter inhibition. Nat Rev Nephrol. 2011; 7:669–674.

18. Seyberth HW, Schlingmann KP. Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects. Pediatr Nephrol. 2011; 26:1789–1802.

19. Colussi G, Bettinelli A, Tedeschi S, De Ferrari ME, Syrén ML, Borsa N, Mattiello C, Casari G, Bianchetti MG. A thiazide test for the diagnosis of renal tubular hypokalemic disorders. Clin J Am Soc Nephrol. 2007; 2:454–460.

20. Nozu K, Iijima K, Kanda K, Nakanishi K, Yoshikawa N, Satomura K, Kaito H, Hashimura Y, Ninchoji T, Komatsu H, et al. The pharmacological characteristics of molecular-based inherited salt-losing tubulopathies. J Clin Endocrinol Metab. 2010; 95:E511–E518.

21. Bettinelli A, Borsa N, Syrén ML, Mattiello C, Coviello D, Edefonti A, Giani M, Travi M, Tedeschi S. Simultaneous mutations in the CLCNKB and SLC12A3 genes in two siblings with phenotypic heterogeneity in classic Bartter syndrome. Pediatr Res. 2005; 58:1269–1273.

22. Nakhoul F, Nakhoul N, Dorman E, Berger L, Skorecki K, Magen D. Gitelman's syndrome: a pathophysiological and clinical update. Endocrine. 2012; 41:53–57.

23. Yoo TH, Lee SH, Yoon K, Baek H, Chung JH, Lee T, Ihm C, Kim M. Identification of novel mutations in Na-Cl cotransporter gene in a Korean patient with atypical Gitelman's syndrome. Am J Kidney Dis. 2003; 42:E11–E16.

24. Monkawa T, Kurihara I, Kobayashi K, Hayashi M, Saruta T. Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome. J Am Soc Nephrol. 2000; 11:65–70.

25. Jang HR, Lee JW, Oh YK, Na KY, Joo KW, Jeon US, Cheong HI, Kim J, Han JS. From bench to bedside: diagnosis of Gitelman's syndrome -- defect of sodium-chloride cotransporter in renal tissue. Kidney Int. 2006; 70:813–817.

26. Maki N, Komatsuda A, Wakui H, Ohtani H, Kigawa A, Aiba N, Hamai K, Motegi M, Yamaguchi A, Imai H, et al. Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome. Nephrol Dial Transplant. 2004; 19:1761–1766.

27. Lin SH, Shiang JC, Huang CC, Yang SS, Hsu YJ, Cheng CJ. Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome. J Clin Endocrinol Metab. 2005; 90:2500–2507.

28. Riveira-Munoz E, Chang Q, Godefroid N, Hoenderop JG, Bindels RJ, Dahan K, Devuyst O. Belgian Network for Study of Gitelman Syndrome. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol. 2007; 18:1271–1283.

29. Abuladze N, Yanagawa N, Lee I, Jo OD, Newman D, Hwang J, Uyemura K, Pushkin A, Modlin RL, Kurtz I. Peripheral blood mononuclear cells express mutated NCCT mRNA in Gitelman's syndrome: evidence for abnormal thiazide-sensitive NaCl cotransport. J Am Soc Nephrol. 1998; 9:819–826.

30. Fukuyama S, Okudaira S, Yamazato S, Yamazato M, Ohta T. Analysis of renal tubular electrolyte transporter genes in seven patients with hypokalemic metabolic alkalosis. Kidney Int. 2003; 64:808–816.

31. Yahata K, Tanaka I, Kotani M, Mukoyama M, Ogawa Y, Goto M, Nakagawa M, Sugawara A, Tanaka K, Shimatsu A, et al. Identification of a novel R642C mutation in Na/Cl cotransporter with Gitelman's syndrome. Am J Kidney Dis. 1999; 34:845–853.

32. Qin L, Shao L, Ren H, Wang W, Pan X, Zhang W, Wang Z, Shen P, Chen N. Identification of five novel variants in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome. Nephrology (Carlton). 2009; 14:52–58.

33. Miao Z, Gao Y, Bindels RJ, Yu W, Lang Y, Chen N, Ren H, Sun F, Li Y, Wang X, et al. Coexistence of normotensive primary aldosteronism in two patients with Gitelman's syndrome and novel thiazide-sensitive Na-Cl cotransporter mutations. Eur J Endocrinol. 2009; 161:275–283.

34. Fukuyama S, Hiramatsu M, Akagi M, Higa M, Ohta T. Novel mutations of the chloride channel Kb gene in two Japanese patients clinically diagnosed as Bartter syndrome with hypocalciuria. J Clin Endocrinol Metab. 2004; 89:5847–5850.