Lessons from Mutations in the Epithelial Na Channel SCNN Found in Human Disease

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Mutations in the human ENaC subunit genes result in inherited diseases characterized by either "gain-of-function" or "loss-of-function" of the epithelial Na+ channel in distal convoluted tubules and collecting duct. Mutations causing overactivity of the Na+ channel result in NaCl retention and hypertension (Liddle's syndrome), whereas other mutations leading to reduction or loss of channel activity result in renal salt wasting and hyperkalemic acidosis (pseu-dohypoaldosteronism type I). These "experiments of nature" provide convinc

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Inside ing evidence that the epithelial Na+ channel genes (SNCC1A, -IB, and -1G) encode the crucial amiloride-sensitive Na+ absorptive channel found in connecting tubules and collecting ducts.

Pseudohypoaldosteronism type 1 is a rare autosomal recessive disease that is characterized by severe neonatal renal salt wasting, hyperkalemia, metabolic acidosis, and unresponsiveness to aldosterone. Mutations have been found in both the alpha- and beta-subunit genes of ENaC and, as expected from the inheritance, affected individuals are homozygous.

Liddle's syndrome is an uncommon cause of familial hypertension that is transmitted in an autosomal dominant pattern. The syndrome is characterized by a defect in renal distal tubular sodium handling, resulting in excessive sodium absorption and concomitant potassium wasting and hypokalemia resembling primary aldosteronism. Serum and urine aldosterone concentrations are, however, low. Rapidly following the molecular cloning of SNCC (1A, IB, and IG) genes, it was shown that Liddle's syndrome is caused by mutations in the beta- and gamma-subunit genes of the human epithelial Na+ channel.

The mutation identified in the original kindred described by Liddle introduces a premature stop codon in the ENaC channel beta-subunit that results in a loss of almost all the COOH-terminus of the encoded protein. When RNA encoding the truncated beta and gamma human ENaC subunits is expressed in X. laevis oocytes, Na+ currents are increased compared to oocytes injected with normal (wild-type) ENaC RNA. This appears to be due, largely, to an increase in the number of active (functional) channels in plasma membranes of oocyes injected with the mutant ENaC. Increases in Na+ current are also seen following expression of subunits with point mutations in a conserved motif located in the region of the subunit COOH" terminus that is absent in the Liddle's mutations. Thus, by deleting or mutating a conserved motif, the number of Na+ channels in the cell membrane is increased leading to enhanced renal Na+ reabsorption. The latter results in a predisposition to develop hypertension. These studies of Liddle's syndrome provide direct genetic and physiological evidence that the ENaC (SCNN) channel subunits form the amiloride diuretic-sensitive Na+ channel expressed in the connecting segment and collecting duct.

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