A DE-NOVO MISSENSE MUTATION OF THE BETA-SUBUNIT OF THE EPITHELIAL SODIUM-CHANNEL CAUSES HYPERTENSION AND LIDDLE SYNDROME, IDENTIFYING A PROLINE-RICH SEGMENT CRITICAL FOR REGULATION OF CHANNEL ACTIVITY

Liddle syndrome is a mendelian form of hypertension characterized by c onstitutively elevated renal Na reabsorption that can result from acti vating mutations in the beta or gamma subunit of the epithelial Na cha nnel, All reported mutations have deleted the last 45-76 normal amino acids from the cytoplasmic C terminus of one of these channel subunits . While these findings implicate these terminal segments in the normal negative regulation of channel activity, they do not identify the ami no acid residues that are critical targets for these mutations. Potent ial targets include the short highly conserved Pro-rich segments prese nt in the C terminus of beta and gamma subunits; these segments are si milar to SH3-binding domains that mediate protein-protein interaction. We now report a kindred with Liddle syndrome in which affected patien ts have a mutation in codon 616 of the beta subunit resulting in subst itution of a Leu for one of these highly conserved Pro residues, The f unctional significance of this mutation is demonstrated both by the fi nding that this is a de novo mutation appearing concordantly with the appearance of Liddle syndrome in the kindred and also by the marked ac tivation of amiloride-sensitive Na channel activity seen in Xenopus oo cytes expressing channels containing this mutant subunit (8.8-fold inc rease compared with control oocytes expressing normal channel subunits ; P = 0.003). These findings demonstrate a de novo missense mutation c ausing Liddle syndrome and identify a critical channel residue importa nt for the normal regulation of Na reabsorption in humans.