Liddle's disease: abnormal regulation of amiloride-sensitive na+ channels by mutation of the beta subunit. Bubien, James K., Iskander I. Ismailov, Bakhram K. Berdiev, Trudy Cornwell, Richard P. Lifton, Catherine M. Fuller, Jean-Michel Achard, Dale J. Benos, David G. Warnock. Depts. of Medicine, Physiology Biophysics, and NRTC, Molecular/Cellular Pathology, Univ. of Alabama at Birmingham and VAMC, Birmingham AL. 35294, Howard Hughes Medical Institute, Departments of Medicine and Genetics, Boyer Center for Molecular Medicine Yale University, New Haven, CT. 06510
APStracts 2:0256C, 1995.
Liddle's disease is a autosomal dominant genetic disorder characterized by severe low renin hypertension ("pseudoaldosteronism") that has been genetically linked to a locus on chromosome 16 encoding the [beta] subunit of an amiloride -sensitive sodium channel (ASSC) (15). Peripheral blood lymphocytes (PBLs) express amiloride-sensitive Na+ channels that are functionally indistinguishable from those expressed by Na+-reabsorbing renal epithelial cells (3, 5). The amiloride-sensitive Na+ conductance in PBLs from affected and unaffected individuals from the original Liddle's pedigree was examined using whole-cell patch clamp. Typically, the basal Na+ currents in cells from affected individuals were maximally activated. Basal Na+ currents in cells from unaffected individuals were minimal, and could be maximally activated by superfusion with 8-CPT-cAMP. Affected cells could not be further stimulated with 8-CPT-cAMP. Superfusion with a supermaximal concentration of amiloride (2 [mu]M) inhibited both the cAMP -activated Na+ conductance in unaffected cells, and the constitutively activated inward conductance in affected cells. Cytosolic addition of a peptide identical to the terminal 10 amino acids (AA) of the truncated [beta] subunit normalized the cAMP-mediated but not the PTX-induced regulation of the mutant ASSCs. The findings show that lymphocyte ASSCs are constitutively activated in affected individuals, that a mutation of the [beta] subunit alters ASSC responsiveness to specific regulatory effectors, and that the cellular mechanism responsible for the pathophysiology of Liddle's disease is abnormal regulation of Na+ channel activity. These findings have important diagnostic and therapeutic implications and provide a cellular phenotype for the diagnosis of pseudoaldosteronism. 

Received 17 March 1995; accepted in final form 20 June 1995.
APS Manuscript Number C152-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 18 July 1995.