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

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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.

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Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.

D B Simon, C Nelson-Williams, M J Bia … (1996)

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na-Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

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Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.

Gerardo Gamba (2005)

Electroneutral cation-Cl(-) cotransporters compose a family of solute carriers in which cation (Na(+) or K(+)) movement through the plasma membrane is always accompanied by Cl(-) in a 1:1 stoichiometry. Seven well-characterized members include one gene encoding the thiazide-sensitive Na(+)-Cl(-) cotransporter, two genes encoding loop diuretic-sensitive Na(+)-K(+)-2Cl(-) cotransporters, and four genes encoding K(+)-Cl(-) cotransporters. These membrane proteins are involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl(-) concentration below or above its electrochemical potential equilibrium. In addition, members of this family play an important role in cardiovascular and neuronal pharmacology and pathophysiology. Some of these cotransporters serve as targets for loop diuretics and thiazide-type diuretics, which are among the most commonly prescribed drugs in the world, and inactivating mutations of three members of the family cause inherited diseases such as Bartter's, Gitelman's, and Anderman's diseases. Major advances have been made in the past decade as consequences of molecular identification of all members in this family. This work is a comprehensive review of the knowledge that has evolved in this area and includes molecular biology of each gene, functional properties of identified cotransporters, structure-function relationships, and physiological and pathophysiological roles of each cotransporter.

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Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.

S. Sanjad, Fiona Karet Frankl, Leila Hamdan … (1996)

Inherited hypokalaemic alkalosis with low blood pressure can be divided into two groups-Gitelman's syndrome, featuring hypocalciuria, hypomagnesaemia and milder clinical manifestations, and Bartter's syndrome, featuring hypercalciuria and early presentation with severe volume depletion. Mutations in the renal Na-Cl cotransporter have been shown to cause Gitelman's syndrome. We demonstrate linkage of Bartter's syndrome to the renal Na-K-2Cl cotransporter gene NKCC2, and identify frameshift or non-conservative missense mutations for this gene that co-segregate with the disease. These findings demonstrate the molecular basis of Bartter's syndrome, provide the basis for molecular classification of patients with inherited hypokalaemic alkalosis, and suggest potential phenotypes in heterozygous carriers of NKCC2 mutations.