A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity.
Liddle syndrome is a mendelian form of hypertension characterized by constitutively elevated renal Na reabsorption that can result from activating mutations in the beta or gamma subunit of the epithelial Na channel. All reported mutations have deleted the last 45-76 normal amino acids from the cytoplasmic C terminus of one of these channel subunits. While these findings implicate these terminal segments in the normal negative regulation of channel activity, they do not identify the amino acid residues that are critical targets for these mutations. Potential targets include the short highly conserved Pro-rich segments present in the C terminus of beta and gamma subunits; these segments are similar to SH3-binding domains that mediate protein-protein interaction. We now report a kindred with Liddle syndrome in which affected patients have a mutation in codon 616 of the beta subunit resulting in substitution of a Leu for one of these highly conserved Pro residues. The functional significance of this mutation is demonstrated both by the finding that this is a de novo mutation appearing concordantly with the appearance of Liddle syndrome in the kindred and also by the marked activation of amiloride-sensitive Na channel activity seen in Xenopus oocytes expressing channels containing this mutant subunit (8.8-fold increase compared with control oocytes expressing normal channel subunits; P = 0.003). These findings demonstrate a de novo missense mutation causing Liddle syndrome and identify a critical channel residue important for the normal regulation of Na reabsorption in humans.
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536-0812, USA.
J H
JH
Hansson
L
L
Schild
Y
Y
Lu
T A
TA
Wilson
I
I
Gautschi
R
R
Shimkets
C
C
Nelson-Williams
B C
BC
Rossier
R P
RP
Lifton
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D002648:Child; D053503:Epithelial Sodium Channels; D004848:Epithelium; D005091:Exons; D005260:Female; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics*; D013577:Syndrome; D014981:Xenopus
D053503:Epithelial Sodium Channels; D011994:Recombinant Proteins; C507048:SCNN1B protein, human; D015222:Sodium Channels