title: Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease.
abstract: 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.
authors.affiliation: Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Abul Kalam
authors.initials: AK
authors.lastname: Azad
authors.forename: Robert
authors.initials: R
authors.lastname: Rauh
authors.forename: François
authors.initials: F
authors.lastname: Vermeulen
authors.forename: Martine
authors.initials: M
authors.lastname: Jaspers
authors.forename: Judit
authors.initials: J
authors.lastname: Korbmacher
authors.forename: Brigitte
authors.initials: B
authors.lastname: Boissier
authors.forename: Laurence
authors.initials: L
authors.lastname: Bassinet
authors.forename: Yann
authors.initials: Y
authors.lastname: Fichou
authors.forename: Marie
authors.initials: M
authors.lastname: des Georges
authors.forename: Frauke
authors.initials: F
authors.lastname: Stanke
authors.forename: Kris
authors.initials: K
authors.lastname: De Boeck
authors.forename: Lieven
authors.initials: L
authors.lastname: Dupont
authors.forename: Miroslava
authors.initials: M
authors.lastname: Balascáková
authors.forename: Lena
authors.initials: L
authors.lastname: Hjelte
authors.forename: Patrick
authors.initials: P
authors.lastname: Lebecque
authors.forename: Dragica
authors.initials: D
authors.lastname: Radojkovic
authors.forename: Carlo
authors.initials: C
authors.lastname: Castellani
authors.forename: Marianne
authors.initials: M
authors.lastname: Schwartz
authors.forename: Manfred
authors.initials: M
authors.lastname: Stuhrmann
authors.forename: Martin
authors.initials: M
authors.lastname: Schwarz
authors.forename: Veronika
authors.initials: V
authors.lastname: Skalicka
authors.forename: Isabelle
authors.initials: I
authors.lastname: de Monestrol
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girodon
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tümmler
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Cassiman
authors.forename: Christoph
authors.initials: C
authors.lastname: Korbmacher
authors.forename: Harry
authors.initials: H
authors.lastname: Cuppens
mesh_terms: 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
chemical_list: D053503:Epithelial Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator