Endocrine Abstracts

Background: Pseudohypoaldosteronism type 1 (PHA1) is a primary form of mineralocorticoid resistance presenting in the newborn with renal salt wasting, failure to thrive and dehydration. Inactivating mutations of the NR3C2 gene, coding for the mineralocorticoid receptor (MR) are responsible for the vast majority of autosomal dominant and sporadic cases of renal PHA1. The underlying pathogenic mechanism involves both haploinsufficiency as well as a dominant negative mechanism. However, ~30% of kindreds with clinical signs of renal PHA1 do not present NR3C2 gene mutations or deletions.

Objective: To assess whether mutations in aldosterone signalling genes could be responsible for renal PHA1.

Design and methods: Five genes involved in the aldosterone-MR epithelial sodium reabsorption pathway (SGK-1, NDRG2, GILZ, NEDD4-2, GPR48) were sequenced in 32 patients with clinical signs and symptoms of renal PHA1 and without NR3C2 mutations.

Results: Different already described intronic and exonic single nucleotide polymorphisms (SNP) were found in the five genes sequenced. The frequency of these SNPs was similar to that previously observed in population studies. Three intronic variations were found in the sequence of NEDD4-2 gene. No disease-causing gene mutation or new SNP were detected in the studied PHA1 patient group.

Conclusions: We present further evidence for locus heterogeneity in PHA1. Our data do not support that SGK-1, NDRG2, NEDD4-2, GILZ or GPR48 gene variations are disease-causing factors in genetically unexplained renal PHA1. Further studies of genes encoding intracellular molecules involved in transduction of the signal from the mineralocorticoid receptor to ENaC are warranted.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.