Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I

Abstract

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.

Regulated acid–base transport in the collecting duct

“…RAAS activation occurs during metabolic acidosis (13,66,80,153) and blockade of the RAAS impairs renal acid excretion during acidosis (72,161). Moreover, deficiency of aldosterone secretion or signaling causes hyperkalemic distal renal tubular acidosis (60,104,161 …”

Genetics of arterial hypertension and hypotension

“…Autosomal dominant and recessive forms of PHAI have been identified (Hanukoglu 1991). The autosomal dominant types result from loss-of-function mutations in one MR gene (Geller et al 1998), which indicates that two functional copies of the MR gene are necessary for regular salt homoeostasis. Salt-rich diets ameliorate the symptoms, and the syndrome itself attenuates with age, nicely illustrating the close interactions of genetic, demographic and environmental factors in blood pressure control.…”

Why is plasma renin activity lower in populations of African origin?

“…69 Indeed, inactivating mutations within the mineralocorticoid gene are known to cause autosomal dominant pseudohypoladosteronism type 1, a mild sodium-losing condition associated with hypotension. 70 As yet, no information is available on the presence of polymorphic variants in this gene in blacks likely to influence sodium excretion and thereby sodium balance. On the other hand, other studies have addressed the question of whether differences in renal sodium handling between blacks and whites might be due to another mineralocorticoid produced in excess in blacks.…”