Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones. Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds. These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity. These findings demonstrate the molecular basis and explain the pathophysiology of this disease.

Pseudohypoaldosteronism type I (PHA1) is characterized by neonatal renal salt wasting with dehydration, hypotension, hyperkalaemia and metabolic acidosis, despite elevated aldosterone levels. Two forms of PHA1 exist. An autosomal recessive form features severe disease with manifestations persisting into adulthood. This form is caused by loss-of-function mutations in genes encoding subunits of the amiloride-sensitive epithelial sodium channel (ENaC; refs 2,3). Autosomal dominant or sporadic PHA1 is a milder disease that remits with age. Among six dominant and seven sporadic PHA1 kindreds, we have found no ENaC gene mutations, implicating mutations in other genes. As ENaC activity in the kidney is regulated by the steroid hormone aldosterone acting through the mineralocorticoid receptor, we have screened the mineralocorticoid receptor gene (MLR) for variants and have identified heterozygous mutations in one sporadic and four dominant kindreds. These include two frameshift mutations (one a de novo mutation), two premature termination codons and one splice donor mutation. These mutations segregate with PHA1 and are not found in unaffected subjects. These findings demonstrate that heterozygous MLR mutations cause PHA1, underscore the important role of mineralocorticoid receptor function in regulation of salt and blood pressure homeostasis in humans and motivate further study of this gene for a potential role in blood pressure variation.