Liddle's disease: Abnormal regulation of amiloride-sensitive Na+ channels by β-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 β-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-chlorophenyl-thio)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 μM) 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 β-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 β-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.
  • Author List

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

  • 270
  • Issue

  • 1 39-1