30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations.

Aldosterone and the mineralocorticoid receptor (MR) are key elements for maintaining fluid and electrolyte homeostasis as well as regulation of blood pressure. Loss-of-function mutations of the MR are responsible for renal pseudohypoaldosteronism type 1 (PHA1), a rare disease of mineralocorticoid resistance presenting in the newborn with weight loss, failure to thrive, vomiting and dehydration, associated with hyperkalemia and metabolic acidosis, despite extremely elevated levels of plasma renin and aldosterone. In contrast, a MR gain-of-function mutation has been associated with a familial form of inherited mineralocorticoid hypertension exacerbated by pregnancy. In addition to rare variants, frequent functional single nucleotide polymorphisms of the MR are associated with salt sensitivity, blood pressure, stress response and depression in the general population. This review will summarize our knowledge on MR mutations in PHA1, reporting our experience on the genetic diagnosis in a large number of patients performed in the last 10 years at a national reference center for the disease. We will also discuss the influence of rare MR variants on blood pressure and salt sensitivity as well as on stress and cognitive functions in the general population.

Two Japanese patients with the renal form of pseudohypoaldosteronism type 1 caused by mutations of NR3C2.

Pseudohypoaldosteronism type 1 (PHA1) is a disease characterized by neonatal salt loss due to aldosterone resistance. Two types of PHA1 are known: an autosomal recessive systemic form and an autosomal dominant renal form. The cause of the renal form of PHA1 is heterozygous mutations in NR3C2, which encodes the mineralocorticoid receptor (MR). We encountered two female Japanese infants with the renal form of PHA1 and analyzed NR3C2. The two patients had poor weight gain, and one was developmentally delayed. Genetic analysis identified one novel mutation (c.492_493insTT, p.Met166LeufsX8) and one previously reported mutation (p.R861X). The two produced a premature stop codon, resulting in haploinsufficiency of the MR. In conclusion, genetic analysis of NR3C2 is useful for diagnosis and planning therapeutic strategies.