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Polymorphisms of Amiloride-Sensitive Sodium Channel Subunits in Five Sporadic Cases of Pseudohypoaldosteronism: Do They Have Pathologic Potential?¹

Department of Physiology, Nippon Medical School (K.A., T.S.), 1–1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan; and the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (K.Z., G.P.C.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Keiko Arai, M.D., Department of Physiology, Nippon Medical School, 1–1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. E-mail: arai_keiko/phys2{at}nms.ac.jp

Pseudohypoaldosteronism (PHA) is characterized by congenital resistance of the kidney and/or other mineralocorticoid target tissues to aldosterone, resulting in excessive salt wasting. Mineralocorticoid receptor (MR) and postreceptor defects in the aldosterone-responsive amiloride-sensitive sodium channel (ENaC) subunits have been suggested as potential loci of the defect in this disease, whereas recently defects in MR and ENaC subunits were reported in familial PHA cases. Here we studied the ENaC subunit , ß, and complementary DNAs (cDNAs) in a series of five sporadic cases of PHA, whose MR cDNA contained nonconservative homozygous (C⁹⁴⁴T⁹⁴⁴, Ala²⁴¹Val²⁴¹) and/or a conservative heterozygous substitutions (A⁷⁶⁰G⁷⁶⁰, Ileu¹⁸⁰Val¹⁸⁰), which, however, were also present at high frequencies in a control population with apparently normal salt conservation. We found a nonconservative substitution (A²⁰⁸⁶G²⁰⁸⁶, Thr⁶⁶³Ala⁶⁶³) in the ENaC in all five of our patients, two of whom were homozygous and three of whom were heterozygous for this alteration, which was also present in the homozygous and heterozygous form in 31% and 64% of control subjects, respectively. We also found a nonconservative homozygous substitution (C¹⁰⁰⁶G¹⁰⁰⁶, Pro³³⁶Ara³³⁶) in the ßENaC and three nonconservative and conservative homozygous substitutions (T⁵⁵⁴A⁵⁵⁴, Trp¹⁷⁸Arg¹⁷⁸; C¹⁵²⁶G¹⁵²⁶, Pro⁵⁰¹Ala⁵⁰¹; T¹⁸⁶²G¹⁸⁶², Ser⁶¹⁴Ala⁶¹⁴) in the ENaC of all five of our patients and in a substantial proportion of control subjects. Interestingly, when the patient group was compared to controls, a significantly increased concurrence of the MR and ENaC polymorphisms was found in the patients (P < 0.025). We conclude that the changes identified in the cDNA of the three ENaC subunits in the patients with sporadic PHA are polymorphisms, which on their own have no apparent pathophysiological significance. We hypothesize, however, that these polymorphisms might influence salt conservation negatively if they are present concurrently with other genetic defects of the MR or other proteins that participate in sodium homeostasis. The latter would be compatible with a sporadic presentation and digenic or multigenic expression and heredity in PHA.

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