Combination of ENaC and CFTR mutations may predispose to cystic fibrosis-like disease

To the Editors:

The epithelial sodium channel (ENaC) is part of the complex protein cystic fibrosis transmembrane conductance regulator (CFTR)-interactome that plays a key role in the composition of the airway surface liquid and the mucociliary clearance in the airways. 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. 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.

We recently completed our previous study by screening exons and flanking intronic sequences of ENaC alpha gene in the previously studied 55 patients (13 males and 42 females) with diffuse idiopathic bronchiectasis and with only one or no CFTR mutation/variant. We found three different intronic sequence variations (c.1242+54C>T, c.1553+32G>A and c.1554-6C>T) that are believed to be not deleterious and two different amino acid changes in heterozygous state in three patients of Caucasian origin: p.V462I in one patient and the p.W493R mutation extensively studied by Azad et al. 2 in two patients. One of those also carried one CFTR variant (IVS8-5T) and one mutation in ENaC beta gene (p.S82C). The main results from these three patients are summarised in table 1⇓.

It has been shown that the common human ENaC alpha polymorphism hαA663T is a functional polymorphism that affects human ENaC surface expression, with lower channel activity and lower apparent number of active channels 3, 4. Therefore, we studied the distribution of the hαA663T genotypes in our group of 55 patients with diffuse bronchiectasis. We did not observe a significant increase in the presence of the hαA663T genotype in our group (A663 allele; 69%) compared with the expected frequency in controls (58–70.8%) 2, 5.

To summarise the results from our 55 patients with bronchiectasis, 10 (18%) patients carried at least one missense mutation in the ENaC alpha (as outlined in this report), beta or gamma genes 1. Among them, six had evidence of abnormal sodium transport, either in the sweat glands (sweat chloride concentration 40–59 mmol·L⁻¹) or in the nasal epithelium (basal nasal potential difference (PD) magnitude >30 mV or <10 mV). Interestingly, three patients were transheterozygotes for CFTR/ENaC mutations or variants: they carried either the p.F508del mutation or the IVS8-5T variant of the CFTR gene and all carried the p.S82C mutation in ENaC beta gene; one of them also carried the p.W493R mutation in ENaC alpha gene (table 1⇑). The basal PD in this patient was normal (-13 mV) and no pharmacological study was performed. However, her sweat test was intermediate (44 mmol·L⁻¹) showing that the combination of the CFTR variant and the ENaC mutations led to functional abnormalities.

Given the CF carrier incidence of ∼3.3% (one out of 30) and the 5T carrier incidence of ∼10%, and the fact that ∼9% of the individuals in the general population is expected to carry a rare ENaC mutation, about one in 334 (0.30%) of individuals are expected to be heterozygous for both a CF-causing CFTR mutation/variant and ENaC missense mutation 2, 6, 7. In 55 patients with diffuse bronchiectasis of unknown origin, we found an unexpected high proportion (5%) of heterozygosity for both a CF-causing CFTR mutation/variant and ENaC mutation. Mutesa et al. 8 recently showed that, among five Rwandan patients with CF-like symptoms, elevated sweat chloride and with only one CFTR mutation identified, two of them carried one missense mutation in the ENaC genes. Taken together, these results suggest that transheterozygosity for ENaC/CFTR mutations or variants may lead to deficient ENaC/CFTR interaction, and abnormal ion transport in the airways and bronchiectasis.

Statement of interest

None declared.