Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na⁺ channel

Liddle's syndrome is an inherited form of hypertension caused by mutations that truncate the C-terminus of human epithelial Na⁺ channel (hENaC) subunits. Expression of truncated β and γ hENaC subunits increased Na⁺ current. However, truncation did not alter single-channel conductance or open state probability, suggesting there were more channels in the plasma membrane. Moreover, truncation of the C-terminus of the β subunit increased apical cell-surface expression of hENaC in a renal epithelium. We identified a conserved motif in the C-terminus of all three subunits that, when mutated, reproduced the effect of Liddle's truncations. Further, both truncation of the C-terminus and mutation of the conserved C-terminal motif increased surface expression of chimeric proteins containing the C-terminus of β hENaC. Thus, by deleting a conserved motif, Liddle's mutations increase the number of Na⁺ channels in the apical membrane, which increases renal Na⁺ absorption and creates a predisposition to hypertension.