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Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I

Abstract

Pseudohypoaldosteronism type I (PHA1) is characterized by neonatal renal salt wasting with dehydration, hypotension, hyperkalaemia and metabolic acidosis, despite elevated aldosterone levels. Two forms of PHA1 exist. An autosomal recessive form features severe disease with manifestations persisting into adulthood1. This form is caused by loss-of-function mutations in genes encoding subunits of the amiloride-sensitive epithelial sodium channel (ENaC; refs 2,3 ). Autosomal dominant or sporadic PHA1 is a milder disease that remits with age. Among six dominant and seven sporadic PHA1 kindreds, we have found no ENaC gene mutations, implicating mutations in other genes. As ENaC activity in the kidney is regulated by the steroid hormone aldosterone acting through the mineralocorticoid receptor4, we have screened the mineralocorticoid receptor gene (MLR) for variants and have identified heterozygous mutations in one sporadic and four dominant kindreds. These include two frameshift mutations (one a de novo mutation), two premature termination codons and one splice donor mutation. These mutations segregate with PHA1 and are not found in unaffected subjects. These findings demonstrate that heterozygous MLR mutations cause PHA1, underscore the important role of mineralocorticoid receptor function in regulation of salt and blood pressure homeostasis in humans and motivate further study of this gene for a potential role in blood pressure variation.

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Figure 1: Mutations in MLR in PHA1 kindreds.

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References

  1. Kuhnle, U. Pseudohypoaldosteronism: mutation found, problem solved? Mol. Cell. Endocrinol. 133, 77–80 (1997).

    Article  CAS  Google Scholar 

  2. Chang, S.S. et al. Mutations in subunits of the epithelial sodium channel cause salt-wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nature Genet. 12, 248–253 ( 1996).

    Article  CAS  Google Scholar 

  3. Strautnieks, S.S., Thompson, R.J., Gardiner, R.M. & Chung, E. A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type I families. Nature Genet. 13, 248–250 (1996).

    Article  CAS  Google Scholar 

  4. Grunder, S. & Rossier, B. A reappraisal of aldosterone effects on the kidney: new insights provided by epithelial sodium channel cloning . Curr. Opin. Nephrol. Hypertens. 6, 35– 39 (1997).

    Article  CAS  Google Scholar 

  5. Beato, M. Gene regulation by steroid hormones. Cell 56, 335– 344 (1989).

    Article  CAS  Google Scholar 

  6. Shapiro, M.B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155–7174 (1987).

    Article  CAS  Google Scholar 

  7. Krawczak, M., Reiss, J. & Cooper, D.N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet. 90, 41–54 (1992).

    Article  CAS  Google Scholar 

  8. Berger, S., Cole, T.J., Schmid, W. & Schütz, G. Analysis of glucocorticoid and mineralocorticoid signalling by gene targeting. Endocr. Res. 22, 641–652 (1996).

    Article  CAS  Google Scholar 

  9. Zennaro, M.C., Borensztein, P., Jeunemaitre, X., Armanini, D. & Soubrier, F. No alteration in the primary structure of the mineralocorticoid receptor in a family with pseudohypoaldosteronism. J. Clin. Endocrinol. Metab. 79, 32–38 ( 1994).

    CAS  Google Scholar 

  10. Komesaroff, P.A., Verity, K. & Fuller, P.J. Pseudohypoaldosteronism: molecular characterization of the mineralocorticoid receptor. J. Clin. Endocrinol. Metab. 79, 27–31 ( 1994).

    CAS  Google Scholar 

  11. Arai, K. et al. No apparent mineralocorticoid receptor defect in a series of sporadic cases of pseudohypoaldosteronism. J. Clin. Endocrinol. Metab. 80, 814–817 (1995).

    CAS  Google Scholar 

  12. Pascoe, L., Curnow, K.M., Slutsker, L., Rosler, A. & White, P.C. Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc. Natl Acad. Sci. USA 89, 4996–5000 (1992).

    Article  CAS  Google Scholar 

  13. Rosler, A. The natural history of salt-wasting disorders of adrenal and renal origin. J. Clin. Endocrinol. Metab. 59, 689–700 (1984).

    Article  CAS  Google Scholar 

  14. Koo, W.W. & Gupta, J.M. Breast milk sodium. Arch. Dis. Child. 57, 500–502 (1982).

    Article  CAS  Google Scholar 

  15. Sippell W.G., Dorr, H.G., Bidlingmaier F. & Knorr, D. Plasma levels of aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, cortisol, and cortisone during infancy and childhood. Ped. Res. 14, 39–46 ( 1980).

    Article  CAS  Google Scholar 

  16. Epple, H.J., Schulzke, J.D., Schmitz, H. & Fromm, M. Enzyme and mineralocorticoid receptor-controlled electrogenic Na+ absorption in human rectum in vitro. Am. J. Physiol. 269, G42– G48 (1995).

    Article  CAS  Google Scholar 

  17. Gomez-Sanchez, E.P., Zhou, M. & Gomez-Sanchez, C.E. Mineralocorticoids, salt and high blood pressure. Steroids 61, 184–188 ( 1996).

    Article  CAS  Google Scholar 

  18. Rodriguez-Soriano, J., Ubetagoyena, M. & Vallo, A. Transtubular potassium concentration gradient: a useful test to estimate renal aldosterone bio-activity in infants and children. Ped. Nephrol. 4, 105–110 (1990).

    Article  CAS  Google Scholar 

  19. Bayer, M. & Kutilek, S. A hereditary form of pseudohypoaldosteronism may be manifested in the course of pyelonephritis. Acta Paed. 82, 504 (1993).

    Article  CAS  Google Scholar 

  20. Petersen, S. et al. Pseudohypoaldosteronism. case report. Acta Paediatr. Scand. 67, 255–261 (1978).

    Article  CAS  Google Scholar 

  21. Zennaro, M.C. et al. Human mineralocorticoid receptor genomic structure and identification of expressed isoforms. J. Biol. Chem. 270, 21016– 21020 (1995).

    Article  CAS  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. Hansson, J.H. et al. A de novo missense mutation of the β subunit of the epithelial sodium channel causes hypertension and Liddle's syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc. Natl Acad. Sci. USA 92, 11495–11499 (1995).

    Article  CAS  Google Scholar 

  24. Lim-Tio, S.S., Keightley, M.C. & Fuller, P.J. Determinants of specificity of transactivation in the mineralocorticoid or glucocorticoid receptor. Endocrinology 138, 2537–2543 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the families for their contribution to this project, H. Craig and F. Karet for helpful discussions and C. Nelson-Williams for DNA preparation and helpful discussions. Supported by an NIH specialized center of research in hypertension. R.P.L. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Richard P. Lifton.

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Geller, D., Rodriguez-Soriano, J., Boado, A. et al. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet 19, 279–281 (1998). https://doi.org/10.1038/966

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