A missense mutation in the extracellular domain of aenac causes liddle syndrome
Liddle syndrome is an autosomal dominant formof hypokalemic hypertension due tomutations in the b- or g-subunit of the epithelial sodium channel (ENaC). Here, we describe a family with Liddle syndrome due to a mutation in aENaC. The proband was referred because of resistant hypokalemic hypertension, suppressed renin and aldosterone, and no mutations in the genes encoding b- or gENaC. Exome sequencing revealed a heterozygous, nonconservative T.C single-nucleotide mutation in aENaC that substituted Cys479 with Arg (C479R). C479 is a highly conserved residue in the extracellular domain of ENaC and likely involved in a disulfide bridge with the partner cysteine C394. In oocytes, the C479R and C394S mutations resulted in similar twofold increases in amiloride-sensitive ENaC current. Quantification of mature cleaved aENaC in membrane fractions showed that the number of channels did not increase with thesemutations. Trypsin, which increases open probability of the channel by proteolytic cleavage, resulted in significantly higher currents in the wild type than in C479R or C394S mutants. In summary, a mutation in the extracellular domain of aENaC causes Liddle syndrome by increasing intrinsic channel activity. This mechanism differs from that of the b- And g-mutations, which result in an increase in channel density at the cell surface. This mutation may explain other cases of patients with resistant hypertension and also provides novel insight into ENaC activation, which is relevant for kidney sodium reabsorption and salt-sensitive hypertension.
|Persistent URL||dx.doi.org/10.1681/ASN.2016111163, hdl.handle.net/1765/102692|
|Journal||American Society of Nephrology. Journal|
Salih, M, Gautschi, I. (Ivan), Van Bemmelen, M.X. (Miguel X.), Benedetto, M.D. (Michael Di), Brooks, A.S. (Alice S.), Lugtenberg, D. (Dorien), … Hoorn, E.J. (2017). A missense mutation in the extracellular domain of aenac causes liddle syndrome. American Society of Nephrology. Journal, 28(11), 3291–3299. doi:10.1681/ASN.2016111163