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.