A novel missense mutation of mineralocorticoid receptor gene in one Japanese family with a renal form of pseudohypoaldosteronism type 1

Pseudohypoaldosteronism type 1 (PHA1) is a rare condition characterized by neonatal salt loss with dehydration, hypotension, hyperkalemia, and metabol ic acidosis, despite elevated plasma aldosterone levels and PRA. Two modes of inheritance of PHA1 have been described: an autosomal dominant form and an autosomal recessive form. An autosomal recessive form manifests severe l ife-long salt wasting resulting from multiple mineralocorticoid target tiss ue such as sweat, salivary glands, the colonic epithelium, and lung. Contra ry, an autosomal dominant PHA1 manifests milder salt wasting that gradually improves with advancing age. Recently, in one sporadic and four dominant c ases, four different mutations including two frame shift mutations, two pre mature termination codons, and one splice site mutation in the mineralocort icoid receptor (R-TR) gene were identified. We studied the molecular mechanisms of one Japanese family with a renal for m of PRA1. FCR and direct sequencing of the MR gene identified a heterozygo us point mutation changing codon 924 Leu (CTG) to CCC(Pro) (L924P) in all a ffected members. COS-1 cells were transfected with expression vectors for e ither wild type or the mutant MR-L924P receptors, together with the reporte r plasmid (glucocorticoid response element tk-CAT). Aldosterone increased C AT activity in cells expressing wild-type receptor, but had no effect in ce lls expressing the mutant receptors. These results suggest that mineralocor ticoid resistance in this family is due to a missense mutation in the MR ge ne. To our knowledge, this is the first case of the missense mutation of th e MR gene in renal PHA1.