Liddle's syndrome caused by a novel missense mutation (P617L) of the epithelial sodium channel beta subunit.
OBJECTIVE
The aim of the study was to search for mutations of SCNN1B and SCNN1G in an Italian family with apparently dominant autosomal transmission of a clinical phenotype consistent with Liddle's syndrome.


METHODS
Genetic analysis was performed in the proband, his relatives, and 100 control subjects. To determine the functional role of the mutation identified in the proband, we expressed the mutant or wild-type epithelial sodium channel in Xenopus laevis oocytes.


RESULTS
A novel point mutation, causing an expected substitution of a leucine residue for the second proline residue of the conserved PY motif (PPP x Y) of the beta subunit was identified in the proband. The functional expression of the mutant epithelial sodium channel in X. laevis oocytes showed a three-fold increase in the amiloride-sensitive current as compared with that of the wild-type channel.


CONCLUSIONS
This newly identified mutation adds to other missense mutations of the PY motif of the beta subunit of the epithelial sodium channel, thus confirming its crucial role in the regulation of the epithelial sodium channel. To our knowledge, this is the first report of Liddle's syndrome in the Italian population, confirmed by genetic and functional analysis, with the identification of a gain-of-function mutation not previously reported.
Rossi
Ermanno
E
Second Unit of Internal Medicine, Department of Internal Medicine, Italy. rossi.ermanno@asmn.re.it
Farnetti
Enrico
E
Debonneville
Anne
A
Nicoli
Davide
D
Grasselli
Chiara
C
Regolisti
Giuseppe
G
Negro
Aurelio
A
Perazzoli
Franco
F
Casali
Bruno
B
Mantero
Franco
F
Staub
Olivier
O
D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007008:Hypokalemia / Q000235:genetics*; D007558:Italy; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D012964:Sodium / Q000378:metabolism*; D013577:Syndrome; D014982:Xenopus laevis
D053503:Epithelial Sodium Channels; C507048:SCNN1B protein, human; C507052:SCNN1G protein, human; D012964:Sodium