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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kuhnle, U. Pseudohypoaldosteronism: mutation found, problem solved? Mol. Cell. Endocrinol. 133, 77–80 (1997).
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).
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).
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).
Beato, M. Gene regulation by steroid hormones. Cell 56, 335– 344 (1989).
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).
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).
Berger, S., Cole, T.J., Schmid, W. & Schütz, G. Analysis of glucocorticoid and mineralocorticoid signalling by gene targeting. Endocr. Res. 22, 641–652 (1996).
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).
Komesaroff, P.A., Verity, K. & Fuller, P.J. Pseudohypoaldosteronism: molecular characterization of the mineralocorticoid receptor. J. Clin. Endocrinol. Metab. 79, 27–31 ( 1994).
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).
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).
Rosler, A. The natural history of salt-wasting disorders of adrenal and renal origin. J. Clin. Endocrinol. Metab. 59, 689–700 (1984).
Koo, W.W. & Gupta, J.M. Breast milk sodium. Arch. Dis. Child. 57, 500–502 (1982).
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).
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).
Gomez-Sanchez, E.P., Zhou, M. & Gomez-Sanchez, C.E. Mineralocorticoids, salt and high blood pressure. Steroids 61, 184–188 ( 1996).
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).
Bayer, M. & Kutilek, S. A hereditary form of pseudohypoaldosteronism may be manifested in the course of pyelonephritis. Acta Paed. 82, 504 (1993).
Petersen, S. et al. Pseudohypoaldosteronism. case report. Acta Paediatr. Scand. 67, 255–261 (1978).
Zennaro, M.C. et al. Human mineralocorticoid receptor genomic structure and identification of expressed isoforms. J. Biol. Chem. 270, 21016– 21020 (1995).
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).
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).
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).
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.
About this article
Physiological Reviews (2019)
Journal of Pediatric Endocrinology and Metabolism (2019)
Seminars in Nephrology (2019)
Pediatric Clinics of North America (2019)