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Different Inactivating Mutations of the Mineralocorticoid Receptor in Fourteen Families Affected by Type I Pseudohypoaldosteronism

Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat (P.S., Y.K., M.-H.L., E.P., M.L., M.-C.Z.), 75018 Paris, France; Division of Nephrology, Robert Debré Hospital (A.-L.L.), 75019 Paris, France; Division of Nephrology (R.S., P.N.) and Division of General Pediatrics (V.A.), Department of Pediatrics, Necker-Enfants Malades Hospital, 75015 Paris, France; Division of Endocrinology (P.S., D.A.), Department of Medical and Surgical Sciences, University of Padova, 35100 Padova, Italy; Division of Pediatric Endocrinology (U.K.), Department of Pediatrics, Ludwig Maximilian University of Munich, 80337 Munich, Germany; Institute G. Gaslini (E.D.B., A.N.), Division of Pediatrics I, 16148 Genova, Italy; Department of Endocrinology (A.M.F., P.L.), Niguarda Ca’Granda Hospital, 20162 Milan, Italy; Henri Mondor Hospital (A.R.), 15002 Aurillac, France; Centro Diagnostico Italiano (M.B.), 20147 Milan, Italy; Department of Internal Medicine (M.C.), Chair of Endocrinology, University Roma "Tor Vergata," 00133 Rome, Italy; Division of Pediatrics (C.D.G.), Orsay General Hospital, 91405 Orsay, France; and Division of Neonatology (V.P-Y., J.P.C.), Le Havre Hospital, 76083 Le Havre, France

Address all correspondence and requests for reprints to: Maria-Christina Zennaro, M.D., Ph.D., Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat, B. P. 416, 16 rue Henri Huchard, 75870 Paris Cedex 18, France. E-mail: zennaro{at}infobiogen.fr.

We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced maximal transactivation, although its binding characteristics and ED₅₀ of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease.

Abbreviations: DBD, DNA binding domain; ENaC, epithelial sodium channel; hMR, human MR; K_d, dissociation constant at equilibrium; LBD, ligand binding domain; MR, mineralocorticoid receptor; MMTV, mouse mammary tumor virus; PHA1, pseudohypoaldosteronism.

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