A novel mutation in the human mineralocorticoid receptor gene in a Japanese family with autosomal-dominant pseudohypoaldosteronism type 1

Pseudohypoaldosteronism type 1 (PHA1) is a rare disease that manifests in infancy with hyponatremia, hyperkalemia, and metabolic acidosis, regardless of renin-angiotensin system (RAS) hyperactivity. PHA1 has autosomal recessive systemic and autosomal dominant renal forms. The systemic form of PHA1 is characterized by severe resistance to aldosterone in multiple organs, including the kidney, colon, sweat and salivary glands, and lung. Patients with renal PHA1 are treated with supplemental oral salt, and they typically show gradual clinical improvement with regard to renal salt loss during childhood. Usually, sodium supplementation becomes unnecessary at one to three years of age (1). Systemic PHA1 is caused by mutations in the amiloride-sensitive luminal sodium channel (ENaC) gene, the protein product of which is responsible for sodium reabsorption. In contrast, in the renal PHA1 form, aldosterone resistance is present only in the kidney. Renal PHA1 results in renal salt loss and failure to thrive during infancy. It is caused by mutations in NR3C2, which encodes the MR. NR3C2 consists of 10 exons; however, the first two (1α and 1β) are not translated. Translation starts from exon 2, which encodes the N-terminal domain (N-ter). Exons 3 and 4 encode the DNA-binding domain (DBD), whereas exons 5-9 encode the C-terminal ligand-binding domain (LBD). In 1998, Geller et al. identified four mutations in human NR3C2: two frameshift mutations and one nonsense mutation in exon 2, and one splicing mutation in intron 5 (2). To date, more than 100 mutations associated with PHA1 have been described (3–8), and several mutations have been identified in the LBD domain. Herein we report a novel mutation in NR3C2 in a Japanese family with renal PHA1. The results provide further information on the clinical consequences of NR3C2 mutations. Received: February 13, 2016 Accepted: July 1, 2016 Corresponding author: Dr. Keisuke Nagasaki, Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata city, Niigata 951-8510, Japan E-mail: [email protected]