Novel mutation in the epithelial sodium channel causing type I pseudohypoaldosteronism in a patient misdiagnosed with cystic fibrosis

Abstract

this patient clearly illustrates the usefulness of genetic confirmation for CF for the diagnosis and genetic counselling, even when it is clinically oriented, and describes a novel mutation of the amiloride-sensitive epithelial sodium channel possibly causing type 1 pseudohypoaldosteronism.

The renal channelopathies

“…The systemic effects of loss of ENaC function include high sweat sodium concentrations (exacerbating renal salt-wasting and creating a tendency to skin infections) and respiratory symptoms (recurrent infections, chronic cough, increased airway secretions), such that it mimics cystic fibrosis. 108 Loss of ENaC function in the collecting duct results in a failure to reabsorb <5% of filtered Na þ , and lack of Na þ influx into principal cells results in a failure to excrete K þ (causing hyperkalaemia, worsened by the lack of responsiveness to aldosterone, the main K þ regulatory hormone), and a failure to excrete H þ by a-intercalated cells (causing metabolic acidosis). Treatment requires lifelong sodium chloride supplementation and strict restriction of dietary potassium intake, together with prophylactic antibiotics for the lung or skin sequelae.…”

Restoration of Epithelial Sodium Channel Function by Synthetic Peptides in Pseudohypoaldosteronism Type 1B Mutants

“…The βG37S mutation, which is equivalent to G70 in the α-subunit and has been electrophysiologically characterized before (Chang et al, 1996 ; Gründer et al, 1997 ; Kucher et al, 2011 ), is located intracellularly in the N-terminal region of the polypeptide chain (Figure 2A ). The αQ101K mutation is located in the first transmembrane region TM1 of α-ENaC toward the extracellular side (Mora-Lopez et al, 2012 ). Mutations in the extracellular loop can be assigned to domains as defined by Jasti et al ( 2007 ) for the X-ray structure of the chicken acid-sensing channel (ASIC1), a homolog of ENaC.…”

“…Q101 is part of the highly conserved “YWQF” motif, and sequence alignment shows that the “YWQF” motif is conserved in different ENaC subunits and species (Mora-Lopez et al, 2012 ). In the case of NMDA receptors it could be demonstrated that the “YWQF” motif is necessary and sufficient to drive their internalization (Scott et al, 2004 ; Lau and Zukin, 2007 ).…”

Exercise Intolerance, Malnutrition, Abnormal Sweat Chloride Levels, and Two CFTR Mutations: Is It Cystic Fibrosis?

“…The authors stated that tables of putative falsepositive sweat tests in several disease states have been directly ''copied and pasted'' from one article or textbook to another without verifying the original literature. On the other hand, false-positive sweat chloride results associated with epithelial sodium channel (ENaC) dysfunction in adrenal insufficiency and pseudohypoaldosteronism are well recognized (Cesur et al, 2000;Mora-Lopez et al, 2012). An abnormal FE1 level associated with a dysfunctional sodium channel was described in one study (Mora-Lopez et al, 2012).…”