Clinical and molecular analysis of six Japanese patients with a renal form of pseudohypoaldosteronism type 1

Abstract

Pseudohypoaldosteronism type 1 (PHA1) is a rare condition characterized by neonatal salt loss with elevated plasma aldosterone and renin levels. Two types of PHA1 have been described: an autosomal recessive systemic form and an autosomal dominant renal form, in which the target organ defect is confined to the renal tubules. The dominant renal form of PHA1 is caused by heterozygous mutations in the NR3C2 gene, which encodes the mineralocorticoid receptor (MR). We determined clinical and biochemical parameters in two familial and four sporadic Japanese patient and analyzed the status of the NR3C2 gene. Failure to thrive was noted in five of the six patients. In one of the familial cases, the mother had an episode of failure to thrive when she was a toddler, but received no medical treatment. NaCl supplementation was discontinued in four of the six patients after they reached one year of age and they have grown normally thereafter. However, in one patient, 9 g/day of salt has been required to maintain serum Na concentration after 1 year of age. Analysis of NR3C2 identified three novel mutations [c. C1951T (p.R651X), c.304_305delGC (p.A102fsX103), c.del 603A (p.T201fsX34)] and one previously reported mutation [c.A2839G (p.947X)]. p.R651X was identified in one familial case and one unrelated sporadic patient. The patient who has been supplemented with large amount of salt was heterozygous for c.del 603A in exon 2. In conclusion, our study expands the spectrum of phenotypes, and characterized mutations of NR3C2 in the renal form of PHA1.

Pseudohypoaldosteronism in a neonate presenting as life-threatening arrhythmia

“…No mutation was reported in their families, which suggests de novo mutation. Therefore, these studies show that renal PHA1 has a broad phenotypic range (6). Some patients with renal PHA1 could even require salt supplementation into the second year of life.…”

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

“…The NR3C2 gene encodes the mineralocorticoid receptor that mediates aldosterone effects on salt and water balance within restricted target cells. Mutations in NR3C2 cause autosomal dominant pseudo hypoaldosteronism type I [46], a disorder characterized by urinary salt wasting. A recent study showed that NR3C2 is downregulated in stable and chronic rejection (CR) patients compared with kidneytransplant recipients with "operational tolerance" [47].…”

Complete clinical resolution of a Japanese family with renal pseudohypoaldosteronism type 1 due to a novel NR3C2 mutation

“…The renal form of adPHA1 (rPHA1) is considered as a mild phenotype of the disease due to renal‐limited mineralocorticoid resistance . Although patients with rPHA1 show severe salt wasting and failure to thrive, such representative clinical pictures subside with age despite persistent elevation of plasma aldosterone level (PAL) . We report a familial case of rPHA1 due to a novel mutation in the nuclear receptor subfamily 3, group C, member 2 gene ( NR3C2 ).…”

“…Autosomal dominant pseudohypoaldosteronism type 1 (adPHA1; OMIM #177735) is a rare condition characterized by congenital resistance to aldosterone resulting in excessive salt wasting . The renal form of adPHA1 (rPHA1) is considered as a mild phenotype of the disease due to renal‐limited mineralocorticoid resistance . Although patients with rPHA1 show severe salt wasting and failure to thrive, such representative clinical pictures subside with age despite persistent elevation of plasma aldosterone level (PAL) .…”