LIDDLES SYNDROME - HERITABLE HUMAN HYPERTENSION CAUSED BY MUTATIONS IN THE BETA-SUBUNIT OF THE EPITHELIAL SODIUM-CHANNEL

Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings sug gesting constitutive activation of the amiloride-sensitive distal rena l epithelial sodium channel. We demonstrate complete linkage of the ge ne encoding the beta subunit of the epithelial sodium channel to Liddl e's syndrome in Liddle's original kindred. Analysis of this gene revea ls a premature stop codon that truncates the cytoplasmic carboxyl term inus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates eit her premature termination or frameshift mutations in this same carboxy -terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epith elial ion channel as well as blood pressure homeostasis.