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Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndrome

Abstract

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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References

  1. 1

    Lifton, R.P. & Jeunemaitre, X. Finding genes that cause human hypertension. J. Hypertension 11, 231–236 (1993).

    CAS  Article  Google Scholar 

  2. 2

    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).

    CAS  Article  Google Scholar 

  3. 3

    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).

    CAS  Article  Google Scholar 

  4. 4

    Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).

    CAS  Article  Google Scholar 

  6. 6

    Leach, F.S. et al. Mutations of a MutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).

    CAS  Article  Google Scholar 

  8. 8

    Lifton, R.P. et al. Hereditary hypertension caused by chimeric gene duplications and ectopic expression of aldosterone synthase. Nature Genet.. 2, 66–74 (1992).

    CAS  Article  Google Scholar 

  9. 9

    Lifton, R.P. et al. A chimaeric 11b-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262–265 (1992).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    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).

    CAS  Google Scholar 

  12. 12

    Canessa, C.M., Horisberger, J.-D. & Rossier, B.C. Epithelial sodium channel related to proteins involved in neurodegeneration. Nature 361, 467–470 (1993).

    CAS  Article  Google Scholar 

  13. 13

    Canessa, C.M. et al. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature 367, 463–467 (1994).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    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).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    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).

    Google Scholar 

  19. 19

    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).

    CAS  Article  Google Scholar 

  20. 20

    Cohen, D., Chumakov, I. & Weissenbach, J. A first-generation physical map of the human genome. Nature 366, 698–701 (1993).

    CAS  Article  Google Scholar 

  21. 21

    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).

    CAS  Article  Google Scholar 

  22. 22

    Jeunemaitre, X. et al. Molecular basis of human hypertension: Role of Angiotensinogen. Cell 71, 169–180 (1992).

    CAS  Article  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    Maniatis, T., Fritsch, E.F., Lauer, J. & Lawn, R.M. The molecular genetics of human hemoglobins. A. Rev. Genet. 14, 145–178 (1980).

    CAS  Article  Google Scholar 

  25. 25

    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).

    Google Scholar 

  26. 26

    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).

    CAS  Article  Google Scholar 

  27. 27

    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).

    CAS  Article  Google Scholar 

  28. 28

    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).

    CAS  Article  Google Scholar 

  29. 29

    Nabika, T. et al. Evaluation of the SA locus in human hypertension. Hypertension. 25, 6–13 (1995).

    CAS  Article  Google Scholar 

  30. 30

    Evans, G.A. & Wahl, G.M. Cosmid vectors for genomic walking and rapid restriction mapping. Meth. Enzymol. 152, 604–610 (1987).

    CAS  Article  Google Scholar 

  31. 31

    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).

    CAS  Article  Google Scholar 

  32. 32

    Gyapay, G. et al. The 1993–94 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).

    CAS  Article  Google Scholar 

  33. 33

    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).

    CAS  Article  Google Scholar 

  34. 34

    Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratories, Cold Spring Harbor, 1989).

    Google Scholar 

  35. 35

    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).

    CAS  Article  Google Scholar 

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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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