Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease.
We investigated whether mutations in the genes that code for the different subunits of the amiloride-sensitive epithelial sodium channel (ENaC) might result in cystic fibrosis (CF)-like disease. In a small fraction of the patients, the disease could be potentially explained by an ENaC mutation by a Mendelian mechanism, such as p.V114I and p.F61L in SCNN1A. More importantly, a more than three-fold significant increase in incidence of several rare ENaC polymorphisms was found in the patient group (30% vs. 9% in controls), indicating an involvement of ENaC in some patients by a polygenetic mechanism. Specifically, a significantly higher number of patients carried c.-55+5G>C or p.W493R in SCNN1A in the heterozygous state, with odds ratios (ORs) of 13.5 and 2.7, respectively.The p.W493R-SCNN1A polymorphism was even found to result in a four-fold more active ENaC channel when heterologously expressed in Xenopus laevis oocytes. About 1 in 975 individuals in the general population will be heterozygous for the hyperactive p.W493R-SCNN1A mutation and a cystic fibrosis transmembrane conductance regulator (CFTR) gene that results in very low amounts (0-10%) functional CFTR. These ENaC/CFTR genotypes may play a hitherto unrecognized role in lung diseases.
Azad
Abul Kalam
AK
Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Rauh
Robert
R
Vermeulen
François
F
Jaspers
Martine
M
Korbmacher
Judit
J
Boissier
Brigitte
B
Bassinet
Laurence
L
Fichou
Yann
Y
des Georges
Marie
M
Stanke
Frauke
F
De Boeck
Kris
K
Dupont
Lieven
L
Balascáková
Miroslava
M
Hjelte
Lena
L
Lebecque
Patrick
P
Radojkovic
Dragica
D
Castellani
Carlo
C
Schwartz
Marianne
M
Stuhrmann
Manfred
M
Schwarz
Martin
M
Skalicka
Veronika
V
de Monestrol
Isabelle
I
Girodon
Emmanuelle
E
Férec
Claude
C
Claustres
Mireille
M
Tümmler
Burkhard
B
Cassiman
Jean-Jacques
JJ
Korbmacher
Christoph
C
Cuppens
Harry
H
D016022:Case-Control Studies; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D053503:Epithelial Sodium Channels / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic
D053503:Epithelial Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator