MUTATIONS IN THE MINERALOCORTICOID RECEPTOR GENE CAUSE AUTOSOMAL-DOMINANT PSEUDOHYPOALDOSTERONISM TYPE-I

Pseudohypoaldosteronism type I (PHA1) is characterized by neonatal ren al salt wasting with dehydration, hypotension, hyperkalaemia and metab olic acidosis, despite elevated aldosterone levels. Two forms of PHA1 exist. An autosomal recessive form features severe disease with manife stations persisting into adulthood(1). This form is caused by toss-of- function mutations in genes encoding subunits of the amiloride-sensiti ve epithelial sodium channel (ENaC; refs 2,3). Autosomal dominant or s poradic PHA1 is a milder disease that remits with age. Among six domin ant and seven sporadic PHA1 kindreds, we have found no ENaC gene mutat ions, implicating mutations in other genes. As ENaC activity in the ki dney is regulated by the steroid hormone aldosterone acting through th e mineralocorticoid receptor(4), we have screened the mineralocorticoi d receptor gene (MLR) for variants and have identified heterozygous mu tations in one sporadic and four dominant kindreds. These include two frameshift mutations tone a de novo mutation), two premature terminati on codons and one splice donor mutation. These mutations segregate wit h PHA1 and are not found in unaffected subjects. These findings demons trate that heterozygous MLR mutations cause PHA1, underscore the impor tant role of mineralocorticoid receptor function in regulation of salt and blood pressure homeostasis in humans and motivate further study o f this gene for a potential role in blood pressure variation.