Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Apr 1;97(7):1780–1784. doi: 10.1172/JCI118606

Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene.

H Tamura 1, L Schild 1, N Enomoto 1, N Matsui 1, F Marumo 1, B C Rossier 1
PMCID: PMC507244  PMID: 8601645

Abstract

Mutations in beta or gamma subunit of the epithelial sodium channel (ENaC) have been found to cause a hereditary form of human hypertension, Liddle syndrome. Most of the mutations reported are either nonsense mutations or frame shift mutations which would truncate the cytoplasmic carboxyl terminus of the beta or gamma subunits of the channel, suggesting that these domains are important for the normal regulation of this channel. We sequenced ENaC in a family with Liddle syndrome and found a missense mutation in beta subunit which predicts substitution of Tyr by His at codon 618, 2 bp downstream from a missense mutation (P616L) that has been reported recently. Presence of this mutation correlates with the clinical manifestations (hypertension, hypokalemia, suppressed aldosterone secretion) in this kindred. Functional expression studies in the Xenopus oocytes revealed constitutive activation of the Y618H mutant indistinguishable from that observed for the deletion mutant (R564stop) identified in the original pedigree of Liddle. Our data suggest that the region between Pro616 and Tyr618 is critically important for regulation of ENaC activity.

Full Text

The Full Text of this article is available as a PDF (213.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Botero-Velez M., Curtis J. J., Warnock D. G. Brief report: Liddle's syndrome revisited--a disorder of sodium reabsorption in the distal tubule. N Engl J Med. 1994 Jan 20;330(3):178–181. doi: 10.1056/NEJM199401203300305. [DOI] [PubMed] [Google Scholar]
  2. Canessa C. M., Horisberger J. D., Rossier B. C. Epithelial sodium channel related to proteins involved in neurodegeneration. Nature. 1993 Feb 4;361(6411):467–470. doi: 10.1038/361467a0. [DOI] [PubMed] [Google Scholar]
  3. Canessa C. M., Schild L., Buell G., Thorens B., Gautschi I., Horisberger J. D., Rossier B. C. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature. 1994 Feb 3;367(6462):463–467. doi: 10.1038/367463a0. [DOI] [PubMed] [Google Scholar]
  4. Cohen G. B., Ren R., Baltimore D. Modular binding domains in signal transduction proteins. Cell. 1995 Jan 27;80(2):237–248. doi: 10.1016/0092-8674(95)90406-9. [DOI] [PubMed] [Google Scholar]
  5. Drubin D. G., Mulholland J., Zhu Z. M., Botstein D. Homology of a yeast actin-binding protein to signal transduction proteins and myosin-I. Nature. 1990 Jan 18;343(6255):288–290. doi: 10.1038/343288a0. [DOI] [PubMed] [Google Scholar]
  6. Hansson J. H., Nelson-Williams C., Suzuki H., Schild L., Shimkets R., Lu Y., Canessa C., Iwasaki T., Rossier B., Lifton R. P. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet. 1995 Sep;11(1):76–82. doi: 10.1038/ng0995-76. [DOI] [PubMed] [Google Scholar]
  7. Hansson J. H., Schild L., Lu Y., Wilson T. A., Gautschi I., Shimkets R., Nelson-Williams C., Rossier B. C., Lifton R. P. A de novo missense mutation of the beta 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 U S A. 1995 Dec 5;92(25):11495–11499. doi: 10.1073/pnas.92.25.11495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Matsumoto P. S., Ohara A., Duchatelle P., Eaton D. C. Tyrosine kinase regulates epithelial sodium transport in A6 cells. Am J Physiol. 1993 Jan;264(1 Pt 1):C246–C250. doi: 10.1152/ajpcell.1993.264.1.C246. [DOI] [PubMed] [Google Scholar]
  9. McDonald F. J., Snyder P. M., McCray P. B., Jr, Welsh M. J. Cloning, expression, and tissue distribution of a human amiloride-sensitive Na+ channel. Am J Physiol. 1994 Jun;266(6 Pt 1):L728–L734. doi: 10.1152/ajplung.1994.266.6.L728. [DOI] [PubMed] [Google Scholar]
  10. Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573–580. doi: 10.1038/373573a0. [DOI] [PubMed] [Google Scholar]
  11. Ren R., Mayer B. J., Cicchetti P., Baltimore D. Identification of a ten-amino acid proline-rich SH3 binding site. Science. 1993 Feb 19;259(5098):1157–1161. doi: 10.1126/science.8438166. [DOI] [PubMed] [Google Scholar]
  12. Rossier B. C., Canessa C. M., Schild L., Horisberger J. D. Epithelial sodium channels. Curr Opin Nephrol Hypertens. 1994 Sep;3(5):487–496. doi: 10.1097/00041552-199409000-00003. [DOI] [PubMed] [Google Scholar]
  13. Rotin D., Bar-Sagi D., O'Brodovich H., Merilainen J., Lehto V. P., Canessa C. M., Rossier B. C., Downey G. P. An SH3 binding region in the epithelial Na+ channel (alpha rENaC) mediates its localization at the apical membrane. EMBO J. 1994 Oct 3;13(19):4440–4450. doi: 10.1002/j.1460-2075.1994.tb06766.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Schild L., Canessa C. M., Shimkets R. A., Gautschi I., Lifton R. P., Rossier B. C. A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5699–5703. doi: 10.1073/pnas.92.12.5699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Shimkets R. A., Warnock D. G., Bositis C. M., Nelson-Williams C., Hansson J. H., Schambelan M., Gill J. R., Jr, Ulick S., Milora R. V., Findling J. W. Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994 Nov 4;79(3):407–414. doi: 10.1016/0092-8674(94)90250-x. [DOI] [PubMed] [Google Scholar]
  16. Voilley N., Lingueglia E., Champigny G., Mattéi M. G., Waldmann R., Lazdunski M., Barbry P. The lung amiloride-sensitive Na+ channel: biophysical properties, pharmacology, ontogenesis, and molecular cloning. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):247–251. doi: 10.1073/pnas.91.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES