NO APPARENT MINERALOCORTICOID RECEPTOR DEFECT IN A SERIES OF SPORADICCASES OF PSEUDOHYPOALDOSTERONISM

Pseudohypoaldosteronism (PHA) is characterized by congenital resistanc e of the kidney and/or other mineralocorticoid target tissues to aldos terone, resulting in excessive salt wasting. Although the mineralocort icoid receptor (MR) was suggested as a potential locus of the defect i n this disease, no such abnormality was found in 3 recently reported c ases, one of whom belongs to this series of 5 patients. Molecular stud ies of the MR complementary DNA and gene in this series of sporadic ca ses of pseudohypoaldosteronism are reported. Four of these patients ha d multiple mineralocorticoid target tissue resistance, whereas 1 had t ransient isolated resistance in the kidney. A nonconservative homozygo us mutation (C-944-->T-944, Ala(241)-->Val(241)) was identified in the complementary DNA of 4 of the patients but was also found in 62 of 10 0 normal alleles. One of these 4 patients had an additional conservati ve heterozygous mutation (A(760)-->G(760), Ileu(180)-->Val(180), which was also present in 11 of 100 normal alleles. None of the patients ha d any abnormalities in the first untranslated exon and 0.9 kilobases o f the 5'-regulatory region of the MR gene, which were fully sequenced and compared with the normal sequence. It is concluded that the mutati ons identified in 4 of these 5 patients with PHA are polymorphisms, wh ich on their own have no apparent pathophysiological significance. It is hypothesized that the defect causing PHA might be in a post-MR step of aldosterone action or in an unsuspected nonclassic receptor for th is hormone.