Liddle's disease: abnormal regulation of amiloride-sensitive Na+ channels by beta-subunit mutation.

Academic Article


  • Liddle's disease is an 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 Na+ channel (ASSC) (15). Peripheral blood lymphocytes (PBL) express ASSC that are functionally indistinguishable from those expressed by Na(+)-reabsorbing renal epithelial cells (3, 5). The amiloride-sensitive Na+ conductance in PBL 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-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (CPT-cAMP). Affected cells could not be further stimulated with CPT-cAMP. Superfusion with a supermaximal concentration of amiloride (2 microM) 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 of the truncated beta-subunit normalized the cAMP-mediated but not the pertussis toxin-induced regulation of the mutant ASSC. The findings show that lymphocyte ASSC 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.
  • Published In


  • Amiloride, Cyclic AMP, Electrophysiology, Humans, Hyperaldosteronism, Hypertension, Lymphocytes, Mutation, Patch-Clamp Techniques, Pertussis Toxin, Renin, Sodium Channels, Thionucleotides, Virulence Factors, Bordetella
  • Digital Object Identifier (doi)

    Author List

  • Bubien JK; Ismailov II; Berdiev BK; Cornwell T; Lifton RP; Fuller CM; Achard JM; Benos DJ; Warnock DG
  • Start Page

  • C208
  • End Page

  • C213
  • Volume

  • 270
  • Issue

  • 1 Pt 1