2009
DOI: 10.1002/humu.21011
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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 … Show more

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Cited by 79 publications
(85 citation statements)
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“…Although it has become wildly recognized that CFTR negatively regulates ENaC function and expression (28), ENaC may also impact on Cl − flux through CFTR. Airwayspecific overexpression of ENaC produces a cystic fibrosis-like phenotype in mice (29), and mutations in amiloride-sensitive epithelial sodium channels are associated with a cystic fibrosis-like disease in patients (30), suggesting that CFTR secretory activity may be inversely regulated by Na + absorption by ENaC. Hence, we considered that the reversal of transepithelial Cl − flux may have been caused by an inhibition of ENaC activity in the presence of an active Na + -K + -ATPase.…”
Section: Discussionmentioning
confidence: 99%
“…Although it has become wildly recognized that CFTR negatively regulates ENaC function and expression (28), ENaC may also impact on Cl − flux through CFTR. Airwayspecific overexpression of ENaC produces a cystic fibrosis-like phenotype in mice (29), and mutations in amiloride-sensitive epithelial sodium channels are associated with a cystic fibrosis-like disease in patients (30), suggesting that CFTR secretory activity may be inversely regulated by Na + absorption by ENaC. Hence, we considered that the reversal of transepithelial Cl − flux may have been caused by an inhibition of ENaC activity in the presence of an active Na + -K + -ATPase.…”
Section: Discussionmentioning
confidence: 99%
“…For example, individuals who are heterozygous for the ⌬F508 mutation in CFTR (cystic fibrosis transmembrane conductance regulator) lack overt pulmonary symptoms. Mutations in ENaC have been reported in individuals with atypical cystic fibrosis who are heterozygous for the ⌬F508 CFTR mutation (49,50). For example, an activating ENaC mutation (␣W493R) that has loss of Na ϩ self-inhibition has been described in this population (39,49).…”
Section: Enac Gain-of-function Polymorphisms and Mutationsmentioning
confidence: 99%
“…Mutations in ENaC have been reported in individuals with atypical cystic fibrosis who are heterozygous for the ⌬F508 CFTR mutation (49,50). For example, an activating ENaC mutation (␣W493R) that has loss of Na ϩ self-inhibition has been described in this population (39,49). At present, it is unclear whether individuals with atypical cystic fibrosis and activating ENaC mutations have elevated blood pressures.…”
Section: Enac Gain-of-function Polymorphisms and Mutationsmentioning
confidence: 99%
“…AZAD et al [2] have also investigated the frequency of ENaC mutations in ENaC alpha, beta and gamma genes in a cohort of 76 patients with cystic fibrosis (CF)-like disease and with only one or no mutation in the CFTR gene. They found a significant increase in missense mutations or variants in patients (15.3%) compared with controls (8.9%) [2]. Moreover, a variant in ENaC alpha gene called p.W493R was found at a more than two-fold significantly increased incidence in patients (8%) compared with controls (3%) and, in the Xenopus laevis oocyte expression system, p.W493R was found to result in a more than four-fold higher ENaC activity.…”
Section: To the Editorsmentioning
confidence: 99%
“…We have recently screened ENaC beta and gamma genes in 55 patients with diffuse bronchiectasis and with only one or no CFTR mutation/variant and showed that eight (15%) patients carried at least one missense mutation in these ENaC genes [1]. AZAD et al [2] have also investigated the frequency of ENaC mutations in ENaC alpha, beta and gamma genes in a cohort of 76 patients with cystic fibrosis (CF)-like disease and with only one or no mutation in the CFTR gene. They found a significant increase in missense mutations or variants in patients (15.3%) compared with controls (8.9%) [2].…”
Section: To the Editorsmentioning
confidence: 99%