Sensitivity of blood pressure to dietary salt is a common feature in subjects with hypertension. These features are exemplified by the mendelian disorder, Liddle's syndrome, previously shown to arise from constitutive activation of the renal epithelial sodium channel due to mutation in the β subunit of this channel. We now demonstrate that this disease can also result from a mutation truncating the carboxy terminus of the γ subunit of this channel; this truncated subunit also activates channel activity. These findings demonstrate genetic heterogeneity of Liddle's syndrome, indicate independent roles of β and γ subunits in the negative regulation of channel activity, and identify a new gene in which mutation causes a salt–sensitive form of human hypertension.
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Lifton, R.P. & Jeunemaitre, X. Finding genes that cause human hypertension. J. Hypertension 11, 231–236 (1993).
Froguel, P. et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356, 162–164 (1992).
Froguel, P. et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. New Engl. J. Med. 328, 697–701 (1993).
Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).
Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).
Leach, F.S. et al. Mutations of a MutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).
Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).
Lifton, R.P. et al. Hereditary hypertension caused by chimeric gene duplications and ectopic expression of aldosterone synthase. Nature Genet.. 2, 66–74 (1992).
Lifton, R.P. et al. A chimaeric 11b-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262–265 (1992).
Shimkets, R.A. et al. Liddle's syndrome: heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel. Cell. 79, 407–414 (1994).
Liddle, G.W., Bledsoe, T. & Coppage, W.S. A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans. Amer. Assoc. Phys. 76, 199–213 (1963).
Canessa, C.M., Horisberger, J.-D. & Rossier, B.C. Epithelial sodium channel related to proteins involved in neurodegeneration. Nature 361, 467–470 (1993).
Canessa, C.M. et al. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature 367, 463–467 (1994).
Canessa, C.M., Merillat, A.-M. & Rossier, B.C. Membrane topology of the epithelial sodium channel in intact cell. Amer. J. Physiol. 267, C1682–C1690 (1994).
Renard, S., Lingueglia, E., Voilley, N., Lazdunski, M. & Barbry, P. Biochemical analysis of the membrane topology of the amiloride-sensitive Na+ channel. J. biol. Chem. 269, 12981–12986 (1994).
Schild, L. et al. A mutation in the epithelial sodium channel causing Liddle's disease increases channel activity in the Xenopus laevis ooocyte expression system. Proc. natn. Acad. Sci. U.S.A. 92, 5699–5703 (1995).
Fukutake, N. et al. A case of Liddle's syndrome with familial occurrence. Nippon Naika Gakkai Zasshi — J. Jap. Soc. Int. Med. 77, 441–442 (1988) (Published in Japanese).
Lifton, R.P. & Dluhy, R.G. Inherited forms of mineralocorticoid hypertension: Glucocorticoid-remediable aldosteronism and the syndrome of apparent mineralocorticoid excess. in Hypertension: Pathophysiology, Diagnosis and Management (eds Laragh, J. & Brenner, B.M.) 2163–2176 (Raven Press, New York, 1995).
Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. natn. Acad. Sci. U.S.A. 86, 2766–2770 (1989).
Cohen, D., Chumakov, I. & Weissenbach, J. A first-generation physical map of the human genome. Nature 366, 698–701 (1993).
Mune, T., Regerson, F.M., Nikkila, H., Agarwal, A.K. & White, P.C. Human hypertension caused by mutations in the kidney isozyme of 11 β-hydroxysteroid dehydrogenase. Nature Genet. 10, 394–399 (1995).
Jeunemaitre, X. et al. Molecular basis of human hypertension: Role of Angiotensinogen. Cell 71, 169–180 (1992).
Sheffield, V., Cox, D.R., Lerman, L.S. & Myers, R.M. Attachment of a 40-base-pair G+C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single base changes. Proc. natn. Acad. Sci. U.S.A. 86, 232–236 (1989).
Maniatis, T., Fritsch, E.F., Lauer, J. & Lawn, R.M. The molecular genetics of human hemoglobins. A. Rev. Genet. 14, 145–178 (1980).
Nathans, J., Sung, C.-H., Weitz, C.J. & Davenport, C.M. Pigments and inherited variation in human vision. J. gen. Physiol. 47, 110–131 (1992).
Samani, N.J. et al. A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure. J. clin. Invest. 92, 1099–1103 (1993).
Harris, E.L., Dene, H. & Rapp, J.P. SA gene and blood pressure cosegregation using Dahl salt-sensitive rats. J. Hypertension 6, 330–334 (1993).
Lindpaintner, K. et al. Molecular genetics of the SA-gene: cosegregation with hypertension and mapping to rat chromsome 1. J. Hypertension 11, 19–23 (1993).
Nabika, T. et al. Evaluation of the SA locus in human hypertension. Hypertension. 25, 6–13 (1995).
Evans, G.A. & Wahl, G.M. Cosmid vectors for genomic walking and rapid restriction mapping. Meth. Enzymol. 152, 604–610 (1987).
Hata, A., Robertson, M., Emi, M. & Lalouel, J.-M. Direct detection and automated sequencing of individual alleles after electrophoretic strand separation:identification of a common nonsense mutation in exon 9 of the human lipoprotein lipase gene. Nucl. Acids Res. 18, 5407–5411 (1990).
Gyapay, G. et al. The 1993–94 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).
Bell, G., Karam, J. & Rutter, W. Polymorphic DNA region adjacent to the 5′ end of the human insulin gene. Proc. natn. Acad. Sci. U.S.A. 78, 5759–5763 (1981).
Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratories, Cold Spring Harbor, 1989).
Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. natn. Acad. Sci. U.S.A. 81, 3443–3446 (1984).
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Hansson, J., Nelson-Williams, C., Suzuki, H. et al. Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 11, 76–82 (1995). https://doi.org/10.1038/ng0995-76
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