title: Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC.
abstract: Aldosterone regulated epithelial sodium channels (ENaC) are constructed of three homologous subunits. Mutations in the alpha-, beta- and gamma-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 beta and gamma 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 beta-ENaC subunits with 253 and 317 residues respectively instead of the 640 residues present in beta-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 beta-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 alpha- and gamma-ENaC subunits. Moreover, these results enhance our understanding of the long-term consequences of these types of mutations in PHA patients.
authors.affiliation: Department of Molecular Biology, Ariel University Center, Ariel, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Edelheit
authors.forename: Israel
authors.initials: I
authors.lastname: Hanukoglu
authors.forename: Yafit
authors.initials: Y
authors.lastname: Shriki
authors.forename: Matanel
authors.initials: M
authors.lastname: Tfilin
authors.forename: Nathan
authors.initials: N
authors.lastname: Dascal
authors.forename: David
authors.initials: D
authors.lastname: Gillis
authors.forename: Aaron
authors.initials: A
authors.lastname: Hanukoglu
mesh_terms: D000818:Animals; D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics / Q000502:physiology; D004553:Electric Conductivity; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014162:Transfection; D014981:Xenopus / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D018389:Codon, Nonsense; D053503:Epithelial Sodium Channels; D020033:Protein Isoforms; D021122:Protein Subunits; C507048:SCNN1B protein, human