Functional polymorphisms in the mineralocorticoid receptor and amirolide-sensitive sodium channel genes in a patient with sporadic pseudohypoaldosteronism

Pseudohypoaldosteronism (PHA) is characterized by urinary salt-wasting in infancy resulting from a congenital resistance to aldosterone involving the genes for the mineralocorticoid receptor (MR) and the amiloride-sensitive sodium channel (ENaC). We identified, in a Japanese patient with sporadic PHA, three homozygous substitutions in the MR gene: G215→C215, A754→G754 (Ile180→Val180), C938→T938 (Ala241→Val241), which had previously been reported to occur in healthy populations. Luciferase activities induced by MR with either G215→C215, Ile180→Val180, or Ala241→Val241 substitution were significantly lower than those for wild-type MR with aldosterone at concentrations ranging from 10–11 to 10–9 M, 10–8 M, or 10–11 to 10–6 M, respectively. A homozygous A→G substitution of the donor splice site of αENaC intron 4 was found in the patient. The corresponding cDNA exhibited a normal structure, suggesting that this substitution does not alter the splice. The results suggest that each of three MR polymorphisms identified in our patient is functionally and structurally heterogeneous. We hypothesize that two or more "functional" polymorphisms, any of which exhibits only slight effects on MR or ENaC function and is alone incapable causing PHA, may in the right allelic combination induce the negative salt-conservation characteristic of PHA.