The maintenance of the proper ionic composition and volume of the intravascular space is critical for normal neuromuscular function and delivery of oxygen and nutrients to tissues. The kidney plays a dominant role in determining the long-term set points of fluid and electrolyte balance, maintaining homeostasis despite wide variation in environmental exposure. Derangements in these components of kidney function are likely to underlie a number of clinical disorders ranging from altered blood pressure due to changes in intravascular volume to abnormalities in electrolyte homeostasis. Examination of inherited disorders of fluid and electrolyte homeostasis provides the opportunity to dissect the fundamental mechanisms governing this process. Identification of underlying genetic defects in such diseases provides novel insight into mechanisms of disease pathogenesis. Moreover, identification of genes in which mutation causes severe clinical disease raises the possibility that more subtle abnormalities in these same genes may underlie less severe but more common disease in the population. They have previously shown that two inherited disorders of increased renal sodium reabsorption, glucocorticoid-remediable aldosteronism and Liddle's syndrome, are caused by mutations that result in increased activity of the renal amiloride-sensitive epithelial sodium channel. Bartter's and Gordon's syndromes are other examples of inherited diseases of renal ion transport having nearly mirror-image phenotypes - the former is characterized by hypokalemia with salt wasting, while the latter features hyperkalemia with increased sodium reabsorption. Bartter's syndrome is itself heterogeneous, with a hypocalciuric variant (Gitelmans' syndrome) and a normal or hypercalciuric variant (true Bartter's syndrome). The pathogenesis of all these disorders has been confounded by the wide range of physiologic abnormalities seen in affected subjects, and the inability to distinguish primary from secondary physiologic changes. By applying genetic approaches to identification of these underlying primary abnormalities, we now show that the autosomal recessive Gitelman's variant of Bartter's syndrome is caused by mutations in the renal thiazide-sensitive Na-Cl cotransporter, indicating that the diverse features found in affected patients are all attributable to primary abnormalities in this protein. This new insight prompts studies ranging from identification of different mutations causing this disease, to expression studies of mutant transporters to assess their function, to clinical studies to assess the effects of these mutations on blood pressure and renal potassium homeostasis in patients with zero, one or two mutations in this gene. We postulate that these mutations in the heterozygous state may lower blood pressure, but also may predispose to development of hypokalemia in some clinical settings. These findings serve as a paradigm for ongoing genetic studies of true Bartter's syndrome and Gordon's syndrome, and provide further evidence of the key role of the kidney in volume and electrolyte homeostasis.
| Simon, D B; Lu, Y; Choate, K A et al. (1999) Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285:103-6 |
