MOLECULAR CHARACTERIZATION OF THE MINERALOCORTICOID RECEPTOR IN PSEUDOHYPOALDOSTERONISM

Pseudohypoaldosteronism (PHA) is characterized by salt-wasting and fai lure to thrive in the newborn, accompanied by high urinary levels of s odium despite hyponatremia, hyperkalemia and metabolic acidosis, eleva tion of plasma renin activity, and high plasma aldosterone levels. PHA patients are resistant to mineralocorticoid administration, but their symptoms ameliorate after a period of sodium supplementation, which c an be discontinued in older subjects. Binding studies performed on mon onuclear leukocytes of the family members affected by the disease have shown the absence of binding of [H-3]aldosterone to the mineralocorti coid receptor (MR) in mononuclear leukocytes in two siblings and a mar ked reduction in another sibling and the father, suggesting either the absence of MR or a defect in the ligand binding domain of the MR in t hese patients. Molecular analysis of the MR in the members of this fam ily did not reveal any major rearrangement or deletion of the MR gene. In addition, no mutation was found in the entire MR coding sequence b y RT-PCR and direct sequencing of MR mRNA, and the semiquantitative RT -PCR analysis of the MR mRNA of one affected patient failed to show an y quantitative abnormality in MR expression. These results do not excl ude a molecular abnormality present in the MR gene being responsible f or PHA. However, they indicate that in this family PHA is not related to a modification of the MR primary structure or to a major abnormalit y in MR expression.