Gitelman syndrome (familial hypokalemia-hypomagnesemia syndrome) is an autosomal recessive inherited renal disorder characterized by defective tubular reabsorption of magnesium and potassium. In this study a group of 18 unrelated and 2 related Gitelman patients, collected from six different countries have been screened for mutations in the human thiazide-sensitive sodium-chloride cotransporter (SLC12A3) gene. Fourteen novel SLC12A3 mutations are presented along with six mutations described earlier, and three neutral polymorphisms. Among the tested patients are two who carry a total of three heterozygous SLC12A3 mutations. Two-thirds of the total number of mutant SLC12A3 alleles are amino acid substitutions. Most SLC12A3 gene mutations, 14 out of a total of 20, are localized at the intracellular carboxy-terminal domain of the NCCT protein. The pathogenicity of individual SLC12A3 mutations is based upon their predicted effect on SLC12A3 protein, and segregation in family members. Evolutionary conservation of substituted amino acid residues and their frequency in control chromosomes is presented. Identical mutations have been found in Gitelman families from different geographical origin, suggesting ancient mutations originating from a common ancestor. As yet, we have not found any evidence for a possible genotype-phenotype correlation.

Antenatal Bartter syndrome is a variant of inherited renal-tubular disorders associated with hypokalemic alkalosis. This disorder typically presents as a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark of this variant is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia. We have analyzed 15 probands belonging to 13 families and have performed SSCP analysis of the coding sequence and the exon-intron boundaries of the NKCC2 gene; and we report 14 novel mutations in patients with antenatal Bartter syndrome, as well as the identification of three isoforms of human NKCC2 that arise from alternative splicing.

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The term "Bartter's syndrome" comprises a set of autosomal recessively inherited renal tubular disorders characterized by hypokalemia, metabolic alkalosis, hyperreninism, and hyperaldosteronism but normal blood pressure. Additional clinical and biochemical features led to a classification into phenotypically different tubulopathies: Gitelman's syndrome, hyperprostaglandin E syndrome (antenatal Bartter's syndrome), and classic Bartter's syndrome. Gitelman's syndrome results from mutations in the SLC12A3 gene encoding the human thiazide-sensitive sodium chloride cotransporter, leading to impaired reabsorption of sodium chloride in the distal convoluted tubule. Genetic heterogeneity of hyperprostaglandin E syndrome has been demonstrated by identification of mutations in the SLC12A1 gene as well as in the KCNJ1 gene. Mutations in SLC12A1 coding for the bumetanide-sensitive sodium potassium 2 chloride cotransporter (NKCC2) cause defective reabsorption of sodium chloride in the thick ascending limb of Henle's loop. Mutations in KCNJ1 leading to loss of function of the potassium channel ROMK disrupt potassium recycling back to the tubule lumen and inhibit thereby the NKCC2 activity. A third gene for hyperprostaglandin E syndrome has been mapped to the short arm of chromosome 1, and it remains to be evaluated whether other genes are involved in the pathogenesis of this disease. Classic Bartter's syndrome has been demonstrated to result from defective chloride transport across the basolateral membrane in the distal nephron due to mutations in the chloride channel gene CLCNKB. This article reviews the molecular genetic approach that has led to identification of genetic defects underlying the different hypokalemic tubulopathies.