The molecular genetic approach to ”Bartter's syndrome"

Abstract

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.

pH gating of ROMK (K ir 1.1) channels: Control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome

“…The inheritance mode of aBS is autosomal recessive, i.e., mutations in both alleles are required for the presentation of symptoms (26). Patients with aBS caused by mutations in the ROMK gene may be homozygous for the mutation, but often carry different mutations on each of the chromosomes (22,24).…”

“…Characteristically, both renal and systemic formation of prostaglandine E 2 are markedly stimulated, resulting in further aggravation of saluretic polyuria, secretory diarrhea, and failure to thrive (25). Analysis of the ROMK gene in individual aBS patients identified a number of point mutations in the core region as well as in the intracellular N and C termini (22,24,26,27). Some of these mutations recently were shown to result in a loss of K ir 1.1 channel function in heterologous expression experiments, although the mechanisms leading to nonfunctional channels are largely unknown (27,28).…”

Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles

“…Bartter's syndrome (38) is an autosomal recessive renal tubulopathy that is characterized by hypokalemic metabolic alkalosis, renal salt wasting, hyperreninemia, and hyperaldosteronism (26, 227,358,618,659). This disease can be classified into four types (I-IV) (583).…”

Molecular Identity and Regulation of Renal Potassium Channels

“…It was shown that this mutation in Kir1.1 leads to a loss of function after expression in COS-7 kidney cells [115]. In TAL, this mutation is believed to affect apical K recycling and to inhibit Na-K-2Cl cotransporter activity [116]. This is the only known inherited malady to involve renal potassium Renal Potassium Channels Table 1.…”