Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism

Abstract

Severe PHA cases are associated with mutations leading to absence of normal-length alpha, beta or gammaENaC, while a mild case has been found to be associated with a missense mutation in alphaENaC. The predominance of PHA-causing mutations in the alphaENaC gene may be related to the function of this subunit.

Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1

“…Previous studies suggest that all stop mutations within the extracellular loop affect ENaC function alike (23,25,26). Only missense mutations in the SCNN1A were found to result in retained channel function (12,27,28).…”

Identification of the roles of conserved charged residues in the extracellular domain of an epithelial sodium channel (ENaC) subunit by alanine mutagenesis

“…In view of this model, it is likely that ENaC functions as a heterotrimer composed of ␣, ␤-, and ␥-ENaC (37). Both molecular genetic studies in humans (7,11,38) and in vitro expression studies (6,12,13,31) indicate that all three subunits are essential for ENaC activity.…”

“…All the hereditary mutations that have been reported in the gene encoding for the ␣-ENaC subunit (SCNN1A) are associated with multisystem type I pseudohypoaldosteronism (PHA) (11). This is a severe salt-wasting disease that can lead to neonatal death, if not diagnosed and treated early (12,14).…”

Pseudohypoaldosteronism in Two Omani Siblings with a Novel Mutation in the SCNN1A Gene

“…No strong genotype/phenotype correlation has yet been established due to the rarity of this condition. However, non-missence mutations resulting in a truncated protein are associated with a more severe disease course [10,11]. In our second case, a novel mutation, c. 385 G > A (p. Gly 129 Ser) in the gene encoding the SCNN1A has been detected, the significance of which is yet uncertain.…”

“…Over twenty genetic mutations causing Systemic Pseudohypoaldosteronism have been detected so far [10,11]. The mutations are in one of the three subunits (SCNN1A, SCNN1B and SCNN1C) of the ENaC responsible for Sodium transport, with the majority affecting the exon 8 of the SCNN1A gene.…”