Abstract
Magnesium plays an essential role in many biochemical and physiological processes. Homeostasis of magnesium is tightly regulated and depends on the balance between intestinal absorption and renal excretion. During the last decades, various hereditary disorders of magnesium handling have been clinically characterized and genetic studies in affected individuals have led to the identification of some molecular components of cellular magnesium transport. In addition to these hereditary forms of magnesium deficiency, recent studies have revealed a high prevalence of latent hypomagnesemia in the general population. This finding is of special interest in view of the association between hypomagnesemia and common chronic diseases such as diabetes, coronary heart disease, hypertension, and asthma. However, valuable methods for the diagnosis of body and tissue magnesium deficiency are still lacking. This review focuses on clinical and genetic aspects of hereditary disorders of magnesium homeostasis. We will review primary defects of epithelial magnesium transport, disorders associated with defects in Ca2+/ Mg2+ sensing, as well as diseases characterized by renal salt wasting and hypokalemic alkalosis, with special emphasis on disturbed magnesium homeostasis.
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References
Cole DE, Quamme GA (2000) Inherited disorders of renal magnesium handling. J Am Soc Nephrol 11:1937–1947
Konrad M, Weber S (2003) Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol 14:249–260
Schimatschek HF, Rempis R (2001) Prevalence of hypomagnesemia in an unselected German population of 16,000 individuals. Magnes Res 14:283–290
Sanders GT, Huijgen HJ, Sanders R (1999) Magnesium in disease: a review with special emphasis on the serum ionized magnesium. Clin Chem Lab Med 37:1011–1033
Saris NE, Mervaala E, Karppanen H, Khawaja JA, Lewenstam A (2000) Magnesium. An update on physiological, clinical and analytical aspects. Clin Chim Acta 294:1–26
Elin RJ (1994) Magnesium: the fifth but forgotten electrolyte. Am J Clin Pathol 102:616–622
Avioli LV, Berman M (1966) Mg28 kinetics in man. J Appl Physiol 21:1688–1694
Seelig MS (1964) The requirement of magnesium by the normal adult. Summary and analysis of. J Am Coll Nutr 14:342–390
EU-SCOF (2001) Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Magnesium. European Commission Health and Consumer Protection Directorate-Generale, Brussels, pp 1–16
Standing Committee on the Scientific Evaluation of Dietary Reference Intakes FNB, Institute of Medicine (1999) Magnesium. In: National Academy of Sciences (ed) Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. National Academies Press, Washington, D.C., pp 190–249
Kerstan D, Quamme G (2002) Physiology and pathophysiology of intestinal absorption of magnesium. In: Massry SG, Morii H, Nishizawa Y (eds) Calcium in internal medicine. Springer-Verlag, London Berlin Heidelberg, pp 171–183
Quamme GA, Rouffignac C de (2000) Epithelial magnesium transport and regulation by the kidney. Front Biosci 5:D694–D711
Fine KD, Santa Ana CA, Porter JL, Fordtran JS (1991) Intestinal absorption of magnesium from food and supplements. J Clin Invest 88:396–402
Rouffignac C de, Quamme G (1994) Renal magnesium handling and its hormonal control. Physiol Rev 74:305–322
Lelievre-Pegorier M, Merlet-Benichou C, Roinel N, Rouffignac C de (1983) Developmental pattern of water and electrolyte transport in rat superficial nephrons. Am J Physiol 245:F15–F21
Dai LJ, Ritchie G, Kerstan D, Kang HS, Cole DE, Quamme GA (2001) Magnesium transport in the renal distal convoluted tubule. Physiol Rev 81:51–84
Quamme GA (1997) Renal magnesium handling: new insights in understanding old problems. Kidney Int 52:1180–1195
Agus ZS (1999) Hypomagnesemia. J Am Soc Nephrol 10:1616–1622
Tsuji H, Venditti FJ Jr, Evans JC, Larson MG, Levy D (1994) The associations of levels of serum potassium and magnesium with ventricular premature complexes (the Framingham Heart Study). Am J Cardiol 74:232–235
Saha H, Harmoinen A, Karvonen AL, Mustonen J, Pasternack A (1998) Serum ionized versus total magnesium in patients with intestinal or liver disease. Clin Chem Lab Med 36:715–718
Hebert P, Mehta N, Wang J, Hindmarsh T, Jones G, Cardinal P (1997) Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test. Crit Care Med 25:749–755
Hashimoto Y, Nishimura Y, Maeda H, Yokoyama M (2000) Assessment of magnesium status in patients with bronchial asthma. J Asthma 37:489–496
Arnold A, Tovey J, Mangat P, Penny W, Jacobs S (1995) Magnesium deficiency in critically ill patients. Anaesthesia 50:203–205
Sutton RA, Domrongkitchaiporn S (1993) Abnormal renal magnesium handling. Miner Electrolyte Metab 19:232–240
Elisaf M, Panteli K, Theodorou J, Siamopoulos KC (1997) Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia. Magnes Res 10:315–320
Tang NL, Cran YK, Hui E, Woo J (2000) Application of urine magnesium/creatinine ratio as an indicator for insufficient magnesium intake. Clin Biochem 33:675–678
Nicoll GW, Struthers AD, Fraser CG (1991) Biological variation of urinary magnesium. Clin Chem 37:1794–1795
Djurhuus MS, Gram J, Petersen PH, Klitgaard NA, Bollerslev J, Beck-Nielsen H (1995) Biological variation of serum and urinary magnesium in apparently healthy males. Scand J Clin Lab Invest 55:549–558
Ryzen E, Elbaum N, Singer FR, Rude RK (1985) Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 4:137–147
Rob PM, Dick K, Bley N, Seyfert T, Brinckmann C, Hollriegel V, Friedrich HJ, Dibbelt L, Seelig MS (1999) Can one really measure magnesium deficiency using the short-term magnesium loading test? J Intern Med 246:373–378
Koo WWK, Tsang RC (1999) Calcium and magnesium homeostasis. In: Avery GB, Fletcher MA, MacDonald MG (eds) Neonatology—pathophysiology and management of the newborn, vol 1. Lippincott Williams and Wilkins, Philadelphia, p 730
Cronan K, Norman ME (2000) Renal and electrolyte emergencies. In: Fleisher GR, Ludwig S (eds) Pediatric emergency medicine, vol 1. Lippincott Williams and Wilkins, Philadelphia, p 827
Gal P, Reed MD (2000) Medications. In: Behrman RE, Kliegman R, Jenson HB (eds) Textbook of pediatrics. Saunders, Philadelphia, p 2270
Ranade VV, Somberg JC (2001) Bioavailability and pharmacokinetics of magnesium after administration of magnesium salts to humans. Am J Ther 8:345–357
Ryan MP (1986) Magnesium and potassium-sparing diuretics. Magnesium 5:282–292
Netzer T, Knauf H, Mutschler E (1992) Modulation of electrolyte excretion by potassium retaining diuretics. Eur Heart J 13 [Suppl G]:22–27
Colussi G, Rombola G, De Ferrari ME, Macaluso M, Minetti L (1994) Correction of hypokalemia with antialdosterone therapy in Gitelman’s syndrome. Am J Nephrol 14:127–135
Bundy JT, Connito D, Mahoney MD, Pontier PJ (1995) Treatment of idiopathic renal magnesium wasting with amiloride. Am J Nephrol 15:75–77
Geven WB, Monnens LA, Willems HL, Buijs WC, Haar BG ter (1987) Renal magnesium wasting in two families with autosomal dominant inheritance. Kidney Int 31:1140–1144
Meij I, Illy KE, Monnens L (2000) Severe hypomagnesemia in a neonate with isolated renal magnesium loss. Nephron 84:198
Meij IC, Saar K, Heuvel LP van den, Nuernberg G, Vollmer M, Hildebrandt F, Reis A, Monnens LA, Knoers NV (1999) Hereditary isolated renal magnesium loss maps to chromosome 11q23. Am J Hum Genet 64:180–188
Meij IC, Koenderink JB, Bokhoven H van, Assink KF, Groenestege WT, Pont JJ de, Bindels RJ, Monnens LA, Heuvel LP van den, Knoers NV (2000) Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit. Nat Genet 26:265–266
Pu HX, Scanzano R, Blostein R (2002) Distinct regulatory effects of the Na,K-ATPase gamma subunit. J Biol Chem 277:20270–20276
Kantorovich V, Adams JS, Gaines JE, Guo X, Pandian MR, Cohn DH, Rude RK (2002) Genetic heterogeneity in familial renal magnesium wasting. J Clin Endocrinol Metab 87:612–617
Geven WB, Monnens LA, Willems JL, Buijs W, Hamel CJ (1987) Isolated autosomal recessive renal magnesium loss in two sisters. Clin Genet 32:398–402
Meij IC, Van Den Heuvel LP, Hemmes S, Van Der Vliet WA, Willems JL, Monnens LA, Knoers NV (2003) Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg(2+) loss. Nephrol Dial Transplant 18:512–516
Michelis MF, Drash AL, Linarelli LG, De Rubertis FR, Davis BB (1972) Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis. (Evaluation of the pathophysiological role of parathyroid hormone.) Metabolism 21:905–920
Manz F, Scharer K, Janka P, Lombeck J (1978) Renal magnesium wasting, incomplete tubular acidosis, hypercalciuria and nephrocalcinosis in siblings. Eur J Pediatr 128:67–79
Rodriguez-Soriano J, Vallo A, Garcia-Fuentes M (1987) Hypomagnesaemia of hereditary renal origin. Pediatr Nephrol 1:465–472
Nicholson JC, Jones CL, Powell HR, Walker RG, McCredie DA (1995) Familial hypomagnesaemia-hypercalciuria leading to end-stage renal failure. Pediatr Nephrol 9:74–76
Praga M, Vara J, Gonzalez-Parra E, Andres A, Alamo C, Araque A, Ortiz A, Rodicio JL (1995) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Kidney Int 47:1419–1425
Benigno V, Canonica CS, Bettinelli A, Vigier RO von, Truttmann AC, Bianchetti MG (2000) Hypomagnesaemia-hypercalciuria-nephrocalcinosis: a report of nine cases and a review. Nephrol Dial Transplant 15:605–610
Weber S, Schneider L, Peters M, Misselwitz J, Ronnefarth G, Boswald M, Bonzel KE, Seeman T, Sulakova T, Kuwertz-Broking E, Gregoric A, Palcoux JB, Tasic V, Manz F, Scharer K, Seyberth HW, Konrad M (2001) Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 12:1872–1881
Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP (1999) Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285:103–106
Wong V, Goodenough DA (1999) Paracellular channels! Science 285:62
Meij IC, Heuvel LP van den, Knoers NV (2002) Genetic disorders of magnesium homeostasis. Biometals 15:297–307
Blanchard A, Jeunemaitre X, Coudol P, Dechaux M, Froissart M, May A, Demontis R, Fournier A, Paillard M, Houillier P (2001) Paracellin-1 is critical for magnesium and calcium reabsorption in the human thick ascending limb of Henle. Kidney Int 59:2206–2215
Müller D, Claverie-Martin F, Eggert P, Garcia-Nieto V (2002) Mutationen im PDZ-Motif von Paracellin-1 als Ursache der Hyperkalziurie im Kindesalter (abstract). Nieren Hochdruckkrankheiten 31:52
Paunier L, Radde IC, Kooh SW, Conen PE, Fraser D (1968) Primary hypomagnesemia with secondary hypocalcemia in an infant. Pediatrics 41:385–402
Anast CS, Mohs JM, Kaplan SL, Burns TW (1972) Evidence for parathyroid failure in magnesium deficiency. Science 177:606–608
Michelis MF, Bragdon RW, Fusco RD, Eichenholz A, Davis BB (1975) Parathyroid hormone responsiveness in hypoparathyroidism with hypomagnesemia. Am J Med Sci 270:412–418
Rude RK, Oldham SB, Singer FR (1976) Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol (Oxf) 5:209–224
Freitag JJ, Martin KJ, Conrades MB, Bellorin-Font E, Teitelbaum S, Klahr S, Slatopolsky E (1979) Evidence for skeletal resistance to parathyroid hormone in magnesium deficiency. Studies in isolated perfused bone. J Clin Invest 64:1238–1244
Cole DE, Kooh SW, Vieth R (2000) Primary infantile hypomagnesaemia: outcome after 21 years and treatment with continuous nocturnal nasogastric magnesium infusion. Eur J Pediatr 159:38–43
Shalev H, Phillip M, Galil A, Carmi R, Landau D (1998) Clinical presentation and outcome in primary familial hypomagnesaemia. Arch Dis Child 78:127–130
Aries PM, Schubert M, Muller-Wieland D, Krone W (2000) Subcutaneous magnesium pump in a patient with combined magnesium transport defect. Dtsch Med Wochenschr 125:970–972
Milla PJ, Aggett PJ, Wolff OH, Harries JT (1979) Studies in primary hypomagnesaemia: evidence for defective carrier-mediated small intestinal transport of magnesium. Gut 20:1028–1033
Matzkin H, Lotan D, Boichis H (1989) Primary hypomagnesemia with a probable double magnesium transport defect. Nephron 52:83–86
Walder RY, Shalev H, Brennan TM, Carmi R, Elbedour K, Scott DA, Hanauer A, Mark AL, Patil S, Stone EM, Sheffield VC (1997) Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint. Hum Mol Genet 6:1491–1497
Walder RY, Borochowitz Z, Shalev H, Carmi R, Elbedour K, Scott DA, Stone EM, Sheffield VC (1999) Hypomagnesemia with secondary hypocalcemia (HSH): narrowing the disease region on chromosome 9 (abstract). Am J Hum Genet 65:A451
Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, Konrad M (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31:166–170
Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R, Sheffield VC (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31:171–174
Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kurosaki T, Kinet JP, Penner R, Scharenberg AM, Fleig A (2001) LTRPC7 is a Mg-ATP-regulated divalent cation channel required for cell viability. Nature 411:590–595
Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366:575–580
Bapty BW, Dai LJ, Ritchie G, Canaff L, Hendy GN, Quamme GA (1998) Activation of Mg2+/Ca2+ sensing inhibits hormone-stimulated Mg2+ uptake in mouse distal convoluted tubule cells. Am J Physiol 275:F353–F360
Hebert SC (1996) Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney. Kidney Int 50:2129–2139
Brown EM, MacLeod RJ (2001) Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 81:239–297
Wang W, Lu M, Balazy M, Hebert SC (1997) Phospholipase A2 is involved in mediating the effect of extracellular Ca2+ on apical K+ channels in rat TAL. Am J Physiol 273:F421–F429
Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG (1993) Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75:1297–1303
Pollak MR, Chou YH, Marx SJ, Steinmann B, Cole DE, Brandi ML, Papapoulos SE, Menko FH, Hendy GN, Brown EM, Seidman CE, Seidman JG (1994) Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 93:1108–1112
Marx SJ, Attie MF, Levine MA, Spiegel AM, Downs RW Jr, Lasker RD (1981) The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore) 60:397–412
Cole DE, Janicic N, Salisbury SR, Hendy GN (1997) Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene. Am J Med Genet 71:202–210
Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG (1994) Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nat Genet 8:303–307
Pearce SH, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, Brown EM, Thakker RV (1996) A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med 335:1115–1122
Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T (2002) Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet 360:692–694
Vargas-Poussou R, Huang C, Hulin P, Houillier P, Jeunemaitre X, Paillard M, Planelles G, Dechaux M, Miller RT, Antignac C (2002) Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. J Am Soc Nephrol 13:2259–2266
Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP (1996) Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 13:183–188
Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP (1996) Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14:152–156
International Collaborative Study Group for Bartter-like Syndromes (1997) Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. International Collaborative Study Group for Bartter-like Syndromes. Hum Mol Genet 6:17–26
Greger R (1985) Ion transport mechanisms in thick ascending limb of Henle’s loop of mammalian nephron. Physiol Rev 65:760–797
Seyberth H, Soergel M, Koeckerling A (1998) Hypokalaemic tubular disorders: the hyperprostaglandin E syndrome and Gitelman-Bartter syndrome. In: Davison A, Cameron J, Grünfeld J, Kerr D, Ritz E, Winearls C (eds) Oxford textbook of clinical nephrology. Oxford University Press, Oxford, pp 1085–1093
Dai LJ, Bapty B, Ritchie G, Quamme GA (1998) PGE2 stimulates Mg2+ uptake in mouse distal convoluted tubule cells. Am J Physiol 275:F833–F839
Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP (1997) Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III. Nat Genet 17:171–178
Konrad M, Vollmer M, Lemmink HH, Van Den Heuvel LP, Jeck N, Vargas-Poussou R, Lakings A, Ruf R, Deschenes G, Antignac C, Guay-Woodford L, Knoers NV, Seyberth HW, Feldmann D, Hildebrandt F (2000) Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol 11:1449–1459
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 48:754–758
Peters M, Jeck N, Reinalter S, Leonhardt A, Tönshoff B, Klaus GG, Konrad M, Seyberth HW (2002) Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med 112:183–190
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 63:24–32
Bartter F, Pronove P, Gill J Jr, MacCardle R (1962) Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 33:811–828
Birkenhager R, Otto E, Schurmann MJ, Vollmer M, Ruf EM, Maier-Lutz I, Beekmann F, Fekete A, Omran H, Feldmann D, Milford DV, Jeck N, Konrad M, Landau D, Knoers NV, Antignac C, Sudbrak R, Kispert A, Hildebrandt F (2001) Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 29:310–314
Estevez R, Boettger T, Stein V, Birkenhager R, Otto E, Hildebrandt F, Jentsch TJ (2001) Barttin is a Cl− channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. Nature 414:558–561
Waldegger S, Jeck N, Barth P, Peters M, Vitzthum H, Wolf K, Kurtz A, Konrad M, Seyberth HW (2002) Barttin increases surface expression and changes current properties of ClC-K channels. Pflugers Arch 444:411–418
Landau D, Shalev H, Ohaly M, Carmi R (1995) Infantile variant of Bartter syndrome and sensorineural deafness: a new autosomal recessive disorder. Am J Med Genet 59:454–459
Jeck N, Reinalter SC, Henne T, Marg W, Mallmann R, Pasel K, Vollmer M, Klaus G, Leonhardt A, Seyberth HW, Konrad M (2001) Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics 108:E5
Gitelman HJ, Graham JB, Welt LG (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79:221–235
Bettinelli A, Bianchetti MG, Girardin E, Caringella A, Cecconi M, Appiani AC, Pavanello L, Gastaldi R, Isimbaldi C, Lama G, et al (1992) Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr 120:38–43
Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB (2001) Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int 59:710–717
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 hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 12:24–30
Yang T, Huang YG, Singh I, Schnermann J, Briggs JP (1996) Localization of bumetanide- and thiazide-sensitive Na-K-Cl cotransporters along the rat nephron. Am J Physiol 271:F931–F939
Reilly RF, Ellison DH (2000) Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol Rev 80:277–313
Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y, Tsukita S (2002) Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol 13:875–886
Loffing J, Loffing-Cueni D, Hegyi I, Kaplan MR, Hebert SC, Le Hir M, Kaissling B (1996) Thiazide treatment of rats provokes apoptosis in distal tubule cells. Kidney Int 50:1180–1190
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 273:29150–29155
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Schlingmann, K.P., Konrad, M. & Seyberth, H.W. Genetics of hereditary disorders of magnesium homeostasis. Pediatr Nephrol 19, 13–25 (2004). https://doi.org/10.1007/s00467-003-1293-z
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DOI: https://doi.org/10.1007/s00467-003-1293-z