Pediatric Nephrology

, Volume 22, Issue 3, pp 326–332 | Cite as

Gitelman’s syndrome: towards genotype-phenotype correlations?

  • Eva Riveira-Munoz
  • Qing Chang
  • René J. Bindels
  • Olivier Devuyst
Editorial Commentary

Abstract

Gitelman’s syndrome (GS) is a salt-losing tubulopathy characterized by hypokalemic alkalosis with hypomagnesemia and hypocalciuria. The disease is associated with inactivating mutations in the SLC12A3 gene that codes for the thiazide-sensitive Na+–Cl cotransporter (NCCT) that is expressed in the apical membrane of the cells lining the distal convoluted tubule (DCT). GS is relatively frequent, and more than 100 mutations scattered through SLC12A3 have been identified thus far. Although the disease is recessively inherited, up to 40% of patients are found to carry only a single mutation, instead of being compound heterozygous or homozygous. The phenotype of GS is highly heterogeneous in terms of age at presentation, and nature/severity of the biochemical abnormalities and clinical manifestations. This phenotypical heterogeneity is observed not only between all patients harbouring SLC12A3 mutations but also among family members or patients with identical mutations. In this review, we discuss the potential explanations for the failure to identify mutant alleles in SLC12A3, as well as the different mechanisms that can account for the inter- and intra-familial phenotype variability in GS, including genetic heterogeneity, position and nature of the mutations, functional consequences, compensatory mechanisms, and modifying genes.

Keywords

Distal convoluted tubule Thiazide diuretic Sodium-chloride cotransporter SLC12A3 Salt-losing nephropathy 

Notes

Acknowledgements

The support of the Belgian agencies FNRS and FRSM, the Foundation Alphonse et Jean Forton, and Concerted Research Actions is acknowledged. The authors apologize for the many relevant publications that could not be referenced because of space limits.

References

  1. 1.
    Gitelman HJ, Graham JB, Welt LG (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79:221–235PubMedGoogle Scholar
  2. 2.
    Jeck N, Schlingmann KP, Reinalter SC, Komhoff M, Peters M, Waldegger S, Seyberth HW (2005) Salt handling in the distal nephron: lessons learned from inherited human disorders. Am J Physiol Regul Integr Comp Physiol 288:R782–R795PubMedGoogle Scholar
  3. 3.
    Bettinelli A, Bianchetti MG, Girardin E, Caringella A, Cecconi M, Appiani AC, Pavanello L, Gastaldi R, Isimbaldi C, Lama G, Marchesoni C, Matteucci C, Patriarca P, DiNatale B, Setzu C, Vitucci P (1992) Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr 120:38–43PubMedCrossRefGoogle Scholar
  4. 4.
    Reinalter SC, Jeck N, Peters M, Seyberth (2004) Pharmacotyping of hypokalaemic salt-losing tubular disorders. Acta Physiol Scand 181:513–521PubMedCrossRefGoogle Scholar
  5. 5.
    Phillips DR, Ahmad KI, Waller SJ, Meisner P, Karet FE (2006) A serum potassium level above 10 mmol/l in a patient predisposed to hypokalemia. Nat Clin Pract Nephrol 2:340–346PubMedCrossRefGoogle Scholar
  6. 6.
    Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitelman HJ, Lifton RP (1996) Gitelman’s variant of Bartter’s syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide sensitive Na-Cl cotransporter. Nat Genet 12:24–30PubMedCrossRefGoogle Scholar
  7. 7.
    Hebert SC, Mount DB, Gamba G (2004) Molecular physiology of cation-coupled Cl cotransport: the SLC12 family. Pflugers Arch 447:580–593PubMedCrossRefGoogle Scholar
  8. 8.
    Gamba G, Saltzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger Ma, Brenner BM, Hebert SC (1993) Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci USA 90:2749–2753PubMedCrossRefGoogle Scholar
  9. 9.
    Reissinger A, Ludwig M, Utsch B, Prömse A, Baulmann J, Weisser B, Vetter H, Kramer HJ, Bokemeyer D (2002) 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 25:354–362PubMedCrossRefGoogle Scholar
  10. 10.
    Lemmink HH, Knoers NV, Karolyi L, van Dijk H, Niaudet P, Antignac C, Guay-Woodford LM, Goodyer PR, Carel JC, Hermes A, Seyberth HW, Monnens LA, van den Heuvel LP (1998) Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int 54:720–730PubMedCrossRefGoogle Scholar
  11. 11.
    Jeck N, Konrad M, Peters M, Weber S, Bonzel KE, Seyberth HW (2000) Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediatr Res 48:754–758PubMedGoogle Scholar
  12. 12.
    Zelikovic I, Szargel R, Hawash A, Labay V, Hatib I, Cohen N, Nakhoul F (2003) A novel mutation in the chloride channel gene CLCNKB as a cause of Gitelman and Bartter syndromes. Kidney Int 63:24–32PubMedCrossRefGoogle Scholar
  13. 13.
    Schlingmann KP, Konrad M, Jeck N, Waldegger P, Reinalter SC, Holder M, Seyberth HW, Waldegger S (2004) Salt wasting and deafness resulting from mutations in two chloride channels. N Engl J Med 350:1314–1319PubMedCrossRefGoogle Scholar
  14. 14.
    Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB; Yale Gitelman’s and Bartter’s Syndrome Collaborative Study Group (2001) Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int 59:710–717PubMedCrossRefGoogle Scholar
  15. 15.
    Peters M, Jeck N, Reinalter S (2002) Clinical presentations of genotypically defined patients with hypokalemic salt-losing tubulopathies. Am J Med 112:183–191PubMedCrossRefGoogle Scholar
  16. 16.
    Pachulski RT, Lopez F, Sharaf R (2005) Gitelman’s not so benign syndrome. N Engl J Med 353:850–851PubMedCrossRefGoogle Scholar
  17. 17.
    Coto E, Rodriguez J, Jeck N, Alvarez V, Stone R, Loris C, Rodriguez LM, Fischbach M, Seyberth HW, Santos F (2004) A new mutation (intron 9+1G>T) in the SLC12A3 gene is linked to Gitelman syndrome in gypsies. Kidney Int 65:25–29PubMedCrossRefGoogle Scholar
  18. 18.
    Lin SH, Cheng NL, Hsu YJ, Halperin ML (2004) Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis 43:304–312PubMedCrossRefGoogle Scholar
  19. 19.
    Verlander JW, Tran TM, Zhang L, Kaplan MR, Hebert SC (1998) Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats. J Clin Invest 101:1661–1669PubMedCrossRefGoogle Scholar
  20. 20.
    Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ (2005) Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 115:1651–1658PubMedCrossRefGoogle Scholar
  21. 21.
    Welsh MJ, Ramsey BW, Accurso F, Cutting GR (2001) Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 5121–5188Google Scholar
  22. 22.
    Hoover RS, Poch E, Monroy A, Vazquez N, Nishio T, Gamba G, Hebert SC (2003) N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(−) cotransporter. J Am Soc Nephrol 14:271–282PubMedCrossRefGoogle Scholar
  23. 23.
    Kunchaparty S, Palcso M, Berkman J, Velazquez H, Desir GV, Bernstein P, Reilly RF, Ellison DH (1999) Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman’s syndrome. Am J Physiol 277:F643–F649PubMedGoogle Scholar
  24. 24.
    de Jong JC, van der Vliet WA, van den Heuvel LP, Willems PH, Knoers NV, Bindels RJ (2002) Functional expression of mutations in the human NaCl cotransporter: evidence for impaired routing mechanisms in Gitelman’s syndrome. J Am Soc Nephrol 13:1442–1448PubMedCrossRefGoogle Scholar
  25. 25.
    Sabath E, Meade P, Berkman J, de los Heros P, Moreno E, Bobadilla NA, Vazquez N, Ellison DH, Gamba G (2004) Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease. Am J Physiol Renal Physiol 287:F195–F203PubMedCrossRefGoogle Scholar
  26. 26.
    Riveira-Munoz E, Dahan K, Godefroid N, Chang Q, HoenderopJG, Bindels RJ, Devuyst O (2006) A new class of mutations involved in Gitelman’s syndrome affects the intrinsic activity of the Na-Cl cotransporter NCCT. Nephrol Dial Transplant 21:iv6Google Scholar
  27. 27.
    de Jong JC, Willems PH, van den Heuvel LP, Knoers NV, Bindels RJ (2003) Functional expression of the human thiazide-sensitive NaCl cotransporter in Madin-Darby canine kidney cells. J Am Soc Nephrol 14:2428–2435PubMedCrossRefGoogle Scholar
  28. 28.
    Schultheis PJ, Lorenz JN, Meneton P, Nieman ML, Riddle TM, Flagella M, Duffy JJ, Doetschman T, Miller ML, Shull GE (1998) Phenotype resembling Gitelman’s syndrome in mice lacking the apical Na+–Cl− cotransporter of the distal convoluted tubule. J Biol Chem 273:29150–29155PubMedCrossRefGoogle Scholar
  29. 29.
    Loffing J, Vallon V, Loffing-Cueni D, Aregger F, Richter K, Pietri L, Bloch-Faure M, Hoenderop JG, Shull GE, Meneton P, Kaissling B (2004) Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman’s syndrome. J Am Soc Nephrol 15:2276–2288PubMedCrossRefGoogle Scholar
  30. 30.
    Morris RG, Hoorn EJ, Knepper MA (2006) Hypokalemia in a mouse model of Gitelman’s syndrome. Am J Physiol Renal Physiol 290:F1416–F1420PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2006

Authors and Affiliations

  • Eva Riveira-Munoz
    • 1
  • Qing Chang
    • 2
  • René J. Bindels
    • 2
  • Olivier Devuyst
    • 1
  1. 1.Division of NephrologyUniversité catholique de Louvain Medical SchoolBrusselsBelgium
  2. 2.Department of Physiology, Nijmegen Centre for Molecular Life SciencesRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

Personalised recommendations