Molecular Genetics of Gitelman Syndrome

Abstract

Gitelman syndrome (OMIM 263800) is an autosomal recessive renal tubular disorder due to loss‐of‐function mutations of SLC12A3 gene, encoding the thiazide‐inhibitable, electroneutral Na+‐Cl cotransporter (NCC) of the distal convoluted tubule. Clinical consequences include chronic normotensive hypokalemic alkalosis, hypomagnesemia, hypocalciuria, polyuria/nocturia, chronic asthenia, muscular cramps, chondrocalcinosis and rarely cardiac arrhythmias.

Impaired reabsorption of glomerular filtrate through NCC drives preferential reabsorption of Na+ in more distal tubular segments via the ‘electrogenic’ channel ENaC, enhancing tubular secretion of potassium and protons, explaining the hypokalemic alkalosis.

There exists wide variability and severity of symptoms between subjects, ranging from an almost asymptomatic disease to a severely disabling one. More than 400 SLC12A3 mutations have been so far described, evenly distributed along the protein sequence and without any hot spot. Mutation detection rate actually is approximately 80–90%. There are no genotype–phenotype correlations.

Commonly considered a benign condition, Gitelman syndrome may be associated with reduced quality of life, increased medicalisation and high hospitalisation rate.

Key Concepts:

  • Gitelman syndrome is the clinical and biochemical manifestation of impaired function of the electroneutral Na‐Cl cotransporter of the renal distal convoluted tubule, the target of the thiazide class of diuretics.

  • Homozygous and compound heterozygous loss‐of‐function mutations of the SLC12A3 gene cause the disease; more than 400 inactivating mutations (mostly missense mutations) have been identified, without any preferential target.

  • Main biochemical abnormalities include hypokalemia, mild metabolic alkalosis, hypomagnesemia, hyperreninemia and hypocalciuria.

  • Clinical manifestations include muscular cramps/tetanic crisis, asthenia, polyuria/nocturia and chondrocalcinosis; normal/low blood pressure is an important feature in the differential diagnosis with hypertensive hypokalemic disorders.

  • Gitelman syndrome cannot be presently cured, and therapy aims at correcting plasma potassium and possibly magnesium levels with supplemental oral potassium and magnesium, aldosterone receptor antagonists and the sodium channel blocker amiloride. Intravenous infusions of potassium and magnesium are needed in acute crisis and stressful contexts.

  • Long‐term prognosis appears good and long‐term renal function preserved, but quality of life may be somehow impaired and medicalisation/hospitalisation rate increased compared to the general population.

Keywords: Gitelman syndrome; renal tubulopathy/tubular disorder; SLC12A3 gene; NCC; hypokalemia; hypocalciuria; metabolic alkalosis; chondrocalcinosis; tetany

Figure 1.

Schematic representation of reabsorptive mechanisms of Na+ and Cl in the distal convoluted tubule (DCT) and in connecting tubule/cortical collecting tubule (CT/CCT). Tubular lumen is on the left and peritubular space on the right. NCC is the electroneutral Na/Cl cotransporter, ENaC is the electrogenic Na transporter, ROMK is the potassium channel and ClC‐Kb is the basolateral chloride channel. Basolateral 3Na+/2K+‐ATPase is shown in black. In the CT/CCT, poor permeability to Cl is the base for a negative luminal electric gradient favouring tubular secretion of positively charged ions K+ and H+ (not shown).

Figure 2.

Schematic and 3D models of NCC protein. (a) Schematic figure of the presumed NCC structure according to the LeuT‐fold model (Data taken from Vargas‐Poussou et al., ; Richardson et al., ; Dimke, ; Castañeda‐Bueno et al., ; Krishnamurthy et al., ; Glaudemann et al., ). (b) 3D model of wild‐type NCC using the Phyre2 (Protein Homology Fold Recognition Engine) server, created by the Structural Bioinformatics Group, Imperial College, London. All *.pdb files generated from Phyre2 were loaded and visualised on the ChemDraw software (Cambridge Software, http://www.cambridgesoft.com). Symbols are as follows: star, SNP rs1529927; numbered spots, the five most common mutations identified in a large cohort of GS patients (1: p.Arg861Cys; 2: p.Leu859Pro; 3: c.1180+1 G>T; 4: p.Cys994Tyr; and 5: p:Gly741Arg); diamond on TM 11, the localisation of the residue responsible for the difference in sensitivity towards thiazides between mammalian and flounder NCC; black dots, conserved phosphorylation sites; open rectangle, γ‐adducin‐binding site; black rombus, residue Gln1030, possibly part of protein–protein interaction motif; Y, glycosylation sites; and open circle, SPAK/OSR1 binding site.

Figure 3.

Patient height (as percentile for Italian population) in 38 paediatric and 42 adult patients with genetically proven GS. Horizontal lines indicate mean values (38 percentile in paediatrics and 45 percentile in adults). A slightly lower height for age in children (mostly in females) appears to be compensated on in later years. Not shown are two children with isolated GH deficit and one with hypothyroidism.

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Further Reading

Bettinelli A, Bianchetti MG, Girardin E et al. (1992) Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkolosis: Bartter and Gitelman syndromes. Journal of Pediatrics 120: 38–43.

Gitelman HJ, Graham JB and Welt LG (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Transactions of the American Association of Physicians 79: 221–223.

Knoers NV and Levtchenko EN (2008) Gitelman syndrome. Orphanet Journal of Rare Diseases 3: 22–27.

OMIM. Gitelman Syndrome. Number entry 263800. http://www.omim.org (accessed 16.07.14).

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Colussi, Giacomo, Tedeschi, Silvana, Bettinelli, Alberto, and Syrén, Marie Louise(Dec 2014) Molecular Genetics of Gitelman Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024287]