Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC

Aldosterone regulated epithelial sodium channels (ENaC) are constructed of three homologous subunits. Mutations in the α-, β- and γ-ENaC subunit genes (SCNN1A, SCNN1B and SCNN1G) are associated with multi-system pseudohypoaldosteronism (PHA), and mutations in the PY motif of carboxy-terminal region of β and γ subunits are associated with Liddle syndrome of hereditary hypertension. In this study we identified two frameshift mutations in the SCNN1B alleles of a female infant diagnosed with multi-system PHA inherited from her parents. This is the first case of PHA in an Ashkenazi family in Israel. The p.Glu217fs (c.648dupA in exon 4) and p.Tyr306fs (c.915delC in exon 6) mutations produce shortened β-ENaC subunits with 253 and 317 residues respectively instead of the 640 residues present in β-ENaC subunit. Expression of cRNAs carrying these mutations in Xenopus oocytes showed that the mutations drastically reduce but do not eliminate ENaC activity. The findings reveal that truncated β-ENaC subunits are capable of partially supporting intracellular transport of the other two subunits to the membrane and the final assembly of a weakly active channel together with normal α- and γ-ENaC subunits. Moreover, these results enhance our understanding of the long-term consequences of these types of mutations in PHA patients.