Open AccessPseudohypoaldosteronism type 1 and Liddle's syndrome mutations that affect the single‐channel properties of the epithelial Na + channel
Author(s) -
Boiko Nina,
Kucher Volodymyr,
Stockand James D.
Publication year - 2015
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12600
Subject(s) - epithelial sodium channel , missense mutation , pseudohypoaldosteronism , gating , mutation , ion channel , medicine , endocrinology , genetics , chemistry , biology , biophysics , gene , aldosterone , sodium , receptor , organic chemistry
Abstract These studies test whether three disease‐causing mutations in genes ( SCNN 1A and SCNN 1G ) encoding subunits of the epithelial Na + channel, EN aC, affect the biophysical and gating properties of this important renal ion channel. The S562P missense mutation in α EN aC and the K106_S108delinsN mutation in γ EN aC are associated with pseudohypoaldosteronism type 1 ( PHA 1). The N530S missense mutation in γ EN aC causes Liddle's syndrome. Incorporation of S562P into α EN aC and K106_S108N into γ EN aC resulted in significant decreases in macroscopic EN aC currents. Conversely, incorporation of N530S into γ EN aC increased macroscopic EN aC current. The S562P substitution resulted in a nonfunctional channel. The K106_S108N mutation produced a functional channel having a normal macroscopic current–voltage relation, there was a slight but significant decrease in unitary conductance and a marked decrease in single‐channel open probability. The N530S substitution increased single‐channel open probability having no effect on the macroscopic current–voltage relation or unitary conductance of the channel. These findings are consistent with mutation of residues at 562 in α EN aC and 530 in γ EN aC, and a 3′ splice site in SCNN 1G (318‐1 G→A; K106_108SdelinsN) resulting in aberrant EN aC activity due to changes in the biophysical and gating properties of the channel. Such changes likely contribute to the cellular mechanism underpinning the PHA 1 and Liddle's syndrome caused by these mutations in EN aC subunits.