A FAMILY WITH LIDDLES-SYNDROME CAUSED BY A NEW MISSENSE MUTATION IN THE BETA-SUBUNIT OF THE EPITHELIAL SODIUM-CHANNEL

Liddle's syndrome is an autosomal dominant form of salt sensitive hype rtension caused by mutations in the beta OF gamma subunit Of the epith elial sodium channel. Systematic mutagenesis studies revealed that a c onserved PPPXY sequence (PY motif) of the C-terminus of the alpha, bet a,or gamma subunits might be involved in the regulation of the channel activity. However, only two missense mutations in the PY motif of the beta subunit have been reported to cause Liddle's syndrome. We sequen ced the C-termini of the beta and gamma subunits of the epithelial sod ium channel in a Japanese family clinically diagnosed as having Liddle 's syndrome and found a new missense mutation in the PY motif of the b eta subunit, P615S. Expression studies with P615S mutant in Xenopus oo cytes resulted in an about 3-fold increase in the amiloride-sensitive- sodium current compared to the wild type (p=0.001). These findings pro vide further clinical evidence for the hypothesis that a conserved PY motif may be critically important for the regulation of the epithelial sodium channel.