Liddle's disease

Abnormal regulation of amiloride-sensitive Na+ channels by β-subunit mutation

James K. Bubien, Iskander I. Ismailov, Bakhram K. Berdiev, Trudy Cornwell, Richard P. Lifton, Catherine M. Fuller, Jean Michel Achard, Dale J. Benos, David G. Warnock

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Volume270
Issue number1 39-1
Publication statusPublished - Jan 1996
Externally publishedYes

Fingerprint

Amiloride
Mutation
Lymphocytes
Liddle Syndrome
Blood
Chromosomes, Human, Pair 16
Inborn Genetic Diseases
Pertussis Toxin
Clamping devices
Pedigree
Chromosomes
Renin
Cyclic AMP
Epithelial Cells
Hypertension
Phenotype
Kidney
Amino Acids
Peptides

Keywords

  • hypertension
  • lymphocytes
  • pseudoaldosteronism
  • whole cell patch clamp

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology
  • Physiology (medical)

Cite this

Bubien, J. K., Ismailov, I. I., Berdiev, B. K., Cornwell, T., Lifton, R. P., Fuller, C. M., ... Warnock, D. G. (1996). Liddle's disease: Abnormal regulation of amiloride-sensitive Na+ channels by β-subunit mutation. American Journal of Physiology - Cell Physiology, 270(1 39-1).

Liddle's disease : Abnormal regulation of amiloride-sensitive Na+ channels by β-subunit mutation. / Bubien, James K.; Ismailov, Iskander I.; Berdiev, Bakhram K.; Cornwell, Trudy; Lifton, Richard P.; Fuller, Catherine M.; Achard, Jean Michel; Benos, Dale J.; Warnock, David G.

In: American Journal of Physiology - Cell Physiology, Vol. 270, No. 1 39-1, 01.1996.

Research output: Contribution to journalArticle

Bubien, JK, Ismailov, II, Berdiev, BK, Cornwell, T, Lifton, RP, Fuller, CM, Achard, JM, Benos, DJ & Warnock, DG 1996, 'Liddle's disease: Abnormal regulation of amiloride-sensitive Na+ channels by β-subunit mutation', American Journal of Physiology - Cell Physiology, vol. 270, no. 1 39-1.
Bubien JK, Ismailov II, Berdiev BK, Cornwell T, Lifton RP, Fuller CM et al. Liddle's disease: Abnormal regulation of amiloride-sensitive Na+ channels by β-subunit mutation. American Journal of Physiology - Cell Physiology. 1996 Jan;270(1 39-1).
Bubien, James K. ; Ismailov, Iskander I. ; Berdiev, Bakhram K. ; Cornwell, Trudy ; Lifton, Richard P. ; Fuller, Catherine M. ; Achard, Jean Michel ; Benos, Dale J. ; Warnock, David G. / Liddle's disease : Abnormal regulation of amiloride-sensitive Na+ channels by β-subunit mutation. In: American Journal of Physiology - Cell Physiology. 1996 ; Vol. 270, No. 1 39-1.
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