Liddle’s syndrome is characterized by hypertension in the setting of hypokalemic metabolic
alkalosis. Clinically these patients resemble those with primary hyperaldosteronism.
However, the hallmark of this disorder is the finding of markedly suppressed serum
aldosterone levels and the lack of response to administration of the mineralocorticoid
receptor blocker spironolactone. In the original classic report of this disorder in
1963, Liddle et al [
1
]concluded that the pathogenesis of this disorder was due to a tendency of the kidney
to conserve Na+ and excrete K+ despite the virtual absence of mineralocorticoids. In the last several years the
specific mechanism underlying this tendency has been elucidated. The disorder has
been localized to a specific mutation in the epithelial Na+ channel located in the
collecting duct of the kidney. This mutation results in constitutive overactivity
of the channel, resulting in a clinical picture virtually identical to that of hyperaldosteronism.
The sequence of events that started with the original report of this disorder and
continued to the present day understanding of the precise molecular defect is illustrative
of how keen clinical deductive reasoning and techniques of molecular biology can complement
each other in enhancing our understanding of a clinical disorder.To read this article in full you will need to make a payment
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References
- A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion.Trans Assoc Am Physicians. 1963; 76: 199-213
- Brief report: Liddle’s syndrome revisited. A disorder of sodium reabsorption in the distal tubule.NEJM. 1994; 330: 178-181
- Liddle’s syndrome.Cell. 1994; 79: 407-414
- Hypertension caused by a truncated epithelial sodium channel γ subunit.Nature Genetics. 1995; 11: 76-82
- Liddle disease caused by a missense mutation of β subunit of the epithelial sodium channel gene.J Clin Invest. 1996; 97: 1780-1784
- Primary aldosteronism.Mayo Clin Proc. 1990; 65: 96-110
- Glucocorticoid-remediable aldosteronism in a large kindred.Ann Intern Med. 1992; 116: 813-820
- On the pathogenesis of metabolic alkalosis in hyperaldosteronism.Am J Med. 1970; 49: 306-315
- Liddle’s syndrome, an uncommon form of hyporeninemic hypoaldosteronism.J Urology. 1987; 137: 636-640
- Escape from the sodium-retaining effects of mineralcorticoids.Kidney Int. 1989; 35: 767-777
- Atrial natriuretic factor significantly contributes to the mineralocorticoid escape phenomenon.J Clin Invest. 1994; 94: 1938-1946
- Epithelial sodium channel related to proteins involved in neurodegeneration.Nature. 1993; 361: 467-470
- Expression cloning of an epithelial amiloride-sensitive Na+ channel.FEBS Lett. 1993; 318: 95-99
- Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.Nature. 1994; 367: 463-467
- Triple-barrel organization of ENaC, a cloned epithelial Na+ channel.J Biolog Chem. 1996; 271: 807-816
- Amiloride-sensitive Na+ channels.News Physiol Sci. 1997; 12: 55-62
- A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system.Proc Natl Acad Sci USA. 1995; 92: 5699-5703
Warnock DG, Bubien JK. Liddle syndrome: clinical and cellular abnormalities. Hosp Practice 1994;July:95–106.
- Liddle’s disease.Am J Physiol. 1996; 270: C208-C213
- Peptide block of constitutively activated Na+ channels in Liddle’s disease.Am J Physiol. 1996; 270: C214-C223
- A de novo missense mutation of the β subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity.Proc Natl Acad Sci USA. 1995; 92: 11495-11499
- Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome.EMBO J. 1996; 15: 2381-2387
- The WW domain.TIBS. 1994; 19: 531-533
- WWP, a new amino acid motif present in single or multiple copies in various proteins including dystrophin and the SH3-binding yes-associated protein YAP65.Biochem Biophys Res Comm. 1994; 205: 1201-1205
- The WW domain of yes-associated protein binds a proline-rich ligand that differs from the consensus established for src homology 3-binding modules.Proc Natl Acad Sci USA. 1995; 92: 7819-7823
- Identification of a set of genes with developmentally down-regulated expression in the mouse brain.Biochem Biophys Res Comm. 1992; 185: 1155-1161
- WW domains off Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle’s syndrome.EMBO J. 1996; 15: 2371-2380
- Synaptotagmin I is a high affinity receptor for clathrin AP-2.Cell. 1994; 78: 751-760
- The HPV-16 E6 and E6-AP complex functions as a ubiquintin-protein ligase in the ubiquitination of p53.Cell. 1993; 75: 495-505
- A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase.Proc Natl Acad Sci USA. 1995; 92: 2563-2567
- The ubiquitin-proteasome proteolytic pathway.Cell. 1994; 79: 13-21
- Mechanism by which Liddle’s syndrome mutations increase activity of a human epithelial Na+ channel.Cell. 1995; 83: 969-978
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© 1998 Elsevier Science Inc. Published by Elsevier Inc. All rights reserved.
