Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel.
Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings suggesting constitutive activation of the amiloride-sensitive distal renal epithelial sodium channel. We demonstrate complete linkage of the gene encoding the beta subunit of the epithelial sodium channel to Liddle's syndrome in Liddle's original kindred. Analysis of this gene reveals a premature stop codon that truncates the cytoplasmic carboxyl terminus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates either premature termination or frameshift mutations in this same carboxy-terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epithelial ion channel as well as blood pressure homeostasis.
Howard Hughes Medical Institute, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
R A
RA
Shimkets
D G
DG
Warnock
C M
CM
Bositis
C
C
Nelson-Williams
J H
JH
Hansson
M
M
Schambelan
J R
JR
Gill
S
S
Ulick
R V
RV
Milora
J W
JW
Findling
D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D018388:Codon, Terminator / Q000235:genetics; D004848:Epithelium; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics*; D006973:Hypertension / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016364:Reading Frames / Q000235:genetics; D011995:Recombination, Genetic; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome
D018388:Codon, Terminator; D005819:Genetic Markers; D015222:Sodium Channels