Disturbances of Na/K Balance
Authors: Olivier Bonny, Bernard C. Rossier
Journal: Journal of the American Society of Nephrology (2002)

Pseudohypoaldosteronism (PHA) is a heterogenous syndrome resulting from the inability for aldosterone to produce one of its physiologic effects, namely the promotion of potassium and hydrogen secretion. It is thus characterized by three essential features: (1) hyperkalemia, (2) metabolic acidosis, and (3) abnormally elevated plasma aldosterone concentrations. It has been classified by Kuhnle (1) into three distinct diseases or types (Table 1).Table 1: The three types of pseudohypoaldosteronismaType I PHA Type I PHA is characterized by early and severe manifestations of salt-wasting, life-threatening hyperkalemia, metabolic acidosis, dehydration, and activation of the renin-angiotensin-aldosterone system (RAAS) associated with normal adrenal function. Plasma aldosterone concentrations are elevated, as is plasma renin activity, thus demonstrating the peripheral resistance of target tissues to these hormones. Treatment by the potent mineralocorticoid fludrocortisone is without effect. Salt supplementation alone is sufficient to compensate for sodium wasting. Type I PHA is heterogeneous and was divided into at least two entities on the basis of inheritance and phenotype of the disease (2). The identification of two distinct genetic defects strengthened this subdivision. Type II PHA PHA II is also known as familial hyperkalemia and hypertension or Gordon syndrome (3,4). The classification of this heterogeneous syndrome as PHA is, however, controversial because plasma aldosterone concentrations are highly variable, usually almost normal, and patients respond adequately to mineralocorticoid hormone (5). The hallmarks of PHA II are hypertension, hyperkalemia, and correction of these abnormalities by low doses of thiazide diuretics (6). Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin activity are also associated with the syndrome. The GFR and adrenal function are normal. An autosomal dominant inheritance has been reported in these families. Three loci were linked to the disease, demonstrating the genetic heterogeneity of the syndrome, which underscores the heterogeneity of the clinical phenotype. Moreover, additional pedigrees with PHA II could not be linked to these loci, implying a wider genetic heterogeneity of the syndrome (7). One locus is on chromosome 1 (8); a second locus is on chromosome 12 (6); the third is on chromosome 17 (6). Interestingly, this latter locus overlaps with a syntenic segment of rat chromosome 10 that contains a BP quantitative trait locus (8). Online Mendelian Inheritance in Man (OMIM) proposes to symbolize the chromosome 1q31-q42 locus involved in type II PHA as PHA2A, the chromosome 17p11-q21 locus as PHA2B, and the locus on chromosome 12p13 by PHA2C. Thanks to the study of a large PHA II kindred, the molecular basis of the syndrome was recently elucidated (9). Mutations or deletions in two members of the WNK serine-threonine kinase family (WNK1 and WNK4) were identified. The precise pathogenic mechanisms by which these mutations or deletions lead to the PHA II phenotype are not yet understood. The deletions (22 and 41 kb) of the intron 1 of the WNK1 gene lead to fivefold overexpression of the WNK1 transcript in leukocytes of affected patients. The WNK1 protein was localized in the cytoplasm of the cells bordering the distal convoluted tubule (DCT), the cortical collecting duct (CC,D) and the medullary collecting duct. Four missense mutations of the WNK4 gene involve a highly conserved coil-coiled region of the protein. Interestingly, the WNK4 protein is expressed both in cytoplasm and at intercellular junctions in the CCD and exclusively in the tight junction complex in the DCT. Further studies are needed for a better understanding of the pathogenesis of this syndrome. Type III PHA Type III PHA is transient and secondary to different pathologies related to kidneys or other organs (Table 1). Rare cases of major intestinal resection (10) or sweat gland dysfunction associated with excessive loss of sodium (11) have been described as leading to PHA III. However, renal causes are encountered more frequently. Nephropathies such as obstructive uropathy (12) or urinary tract infections (13) were reported as causes of transient aldosterone resistance (1). The main characteristic of this type of PHA is a decreased GFR. The mechanism of the renal aldosterone resistance is not well understood, but a relationship between the increase in amounts of transforming growth factor–β (TGF-β) produced in inflammatory states and the known inhibitory effect of TGF-β on the sensitivity of the collecting duct to aldosterone has been suggested (5,14). PHA-1 and PHA III share common features and are primarily salt-losing syndromes. PHA II is a salt-retaining syndrome with a hypertensive phenotype. As discussed below, we propose to abandon this classification and restrict the discussion to PHA as a salt-losing syndrome with strong activation of RAAS. In this review, we will focus on PHA-1, and we will discuss the molecular basis of the disease in describing the relevant molecular mechanisms that allow mineralocorticoid-dependent Na/K balance that takes place in CCD. We will then discuss the genetic basis of the two forms of PHA-1 in an attempt to understand the pathogenic mechanisms of the disease. Sodium and Potassium Balance: Aldosterone Control The final concentration of sodium and potassium in urine is determined during its passage through the collecting duct; this process is mainly controlled by aldosterone (15). In the collecting duct, sodium is reabsorbed from the urinary lumen into the extracellular compartment through a tight epithelium formed by principal and intercalated cells. Aldosterone-dependent, amiloride-sensitive electrogenic sodium transport takes place in the principal cell and is generated by the selective entry of sodium trough an epithelial sodium channel (ENaC) located at the apical membrane. Sodium is then actively extruded out of the cell by the sodium pump or Na,K-ATPase restricted to the basolateral membrane. This electrogenic sodium transport is the driving force for the coupled secretion of potassium through a selective potassium channel (ROMK1) co-expressed at the apical membrane with ENaC. The classic model of the mechanism of aldosterone action in tight epithelia proposes the following steps: aldosterone crosses the plasma membrane and binds to its cytosolic receptor, either the mineralocorticoid (MR) or glucocorticoid (GR) receptor. MR and GR are protected from illicit occupation by high levels of plasma glucocorticoids (cortisol or corticosterone) thanks to the metabolizing action of 11-β-HSD2, which transforms the active cortisol into cortisone, an inactive metabolite that is unable to bind to either MR or GR (16,17). The receptor-hormone complex is translocated to the nucleus, where it interacts with the promoter region of target genes activating or repressing their transcriptional activity. Aldosterone-induced or -repressed proteins (AIPs or ARPs) mediate an increase in transepithelial sodium transport. Early effects are produced by the activation of preexisting transport proteins (ENaC, Na,K-ATPase) via yet-uncharacterized mediators (15). We will discuss MR and ENaC as the two key limiting factors in aldosterone action that are mutated in PHA-1 and emphasize the main features relevant to understand the pathophysiology of the disease. Mineralocorticoid Receptor General Features. A number of excellent reviews have recently been published in this field (15,18–21). We will describe some essential features of the structure and the function of the mineralocorticoid receptors that are necessary to understand the pathophysiology of PHA-1. There are two types of classical corticosteroid receptors: the high-affinity type 1 or mineralocorticoid receptor (MR [22]) and the lower affinity type 2 or glucocorticoid receptor (GR [23]), which are structurally highly homologous. The glucocorticosteroid hormone cortisol (corticosterone in rodents) binds to MR with a high affinity that is similar to that of the mineralocorticoid hormone aldosterone (24); conversely, aldosterone binds to the human GR with a lower affinity that is similar to that of cortisol. Molecular cloning of the glucocorticoid and mineralocorticoid receptors allowed the determination of their primary amino acid structures and prediction of common functional domains. GR and MR display a high degree of identity in their amino acid sequences, with the exception of the variable N-terminal region. The human MR gene encodes a protein of 984 amino acid residues with a predicted molecular size of 107 kD. Structurally and functionally defined domains are observed within the MR and GR receptors (25). The amino-terminal part contains the domain A/B, which is involved in transcriptional activation. The central part includes the DNA-binding domain (DBD or C), which is responsible for DNA binding and recognition of the specific HRE sequences. It consists of two zinc fingers and represents the most highly conserved part of the molecule. Domain E, which represents the ligand-binding domain (LBD or E) also contains sequences that are involved in nuclear translocation, receptor dimerization, hormone-regulated transactivation, and interaction with heat shock proteins. Ligand Binding Domain. The crystal structure of different nuclear receptors is known (26). The human MR LBD has not yet been crystallized but has been modeled on the basis of the retinoic acid receptor gamma and the progesterone receptor crystal structure, allowing for good predictions on the structure-function relationship of the ligand binding pocket and on the specific requirements for binding agonists or antagonists (18,21). Upon binding to an agonist, the receptor undergoes a major conformational change (transconformation). A number of contact sites are required for proper transconformation and have been identified by site-directed mutagenesis (27) and by the discovery of a gain-of-function mutation leading to a constitutively active receptor causing a severe hypertensive phenotype in pregnant women (28). DNA Binding. Dimerization of steroid receptor is a prerequisite for binding to specific hormone-responsive elements (HRE) lying in the promoter region of the target gene. In aldosterone target cells, MR is always coexpressed with GR (no tissue expresses only MR), and it has been proposed that MR can heterodimerize with GR, allowing more diversity in the physiologic response to mineralo- or glucocorticoid hormones, but the in vivo relevance of the phenomenon remains to be established (29,30). Epithelial Sodium Channel (ENaC) ENaC is characterized by a high selectivity for sodium over potassium, a low unitary conductance, long open and closed time, and a high affinity for the potassium-sparing diuretics amiloride and triamterene (31). The genes coding for ENaC were identified by functional expression cloning (32–34). Genes coding for ENaC are members of the DEG/ENaC family that include genes involved in mechanosensation, neurodegeneration, epithelial sodium transport, or pH sensation (see reference 35 for review). Subunit Topology and Stoechiometry. ENaC is a heteromultimeric protein made of three subunits, termed α, β, and γ ENaC (34). All three subunits share about 35% homology at the amino acid level and adopt the same topology, with two transmembrane domains, short intracellular amino- and carboxy- ends and a large extracellular loop corresponding to about 70% of the protein mass. When all three subunits are expressed in the same cell, they assemble according to a preferential heterotetrameric structure (36). The number of subunits lining the pore is still under debate. Four (αβαγ) (36–38), eight (39), or nine (α3β3γ3) (40) subunits stoechiometries were proposed for ENaC. A homotetrameric stoechiometry for a related member of the same gene family, the FMRF-amide-gated sodium channel (FaNaC) cloned in Helix Aspersa, has been proposed (41). Specific Role of αENaC Subunit in the Channel Complex. If all three subunits are homologous and participate in the pore structure, they do not have the same relative function. When injected alone in the Xenopus oocyte, the α subunit produces small but significant amiloride-sensitive sodium currents (32). By contrast, neither β nor γ alone are able to induce similar currents. When αβ or αγ are co-injected in the oocyte, the measured sodium current reached 30% and 10% of wild-type currents respectively, but with a 2-d delay in the appearance of the maximal current (Figure 1) (42). In oocytes injected with β and γ subunits together, small but significant amiloride-sensitive sodium currents are recorded, reaching about 3 to 5% of wild-type currents. They appear with a long delay (5 to 6 d) compared with wild type. Binding experiments demonstrated a close correlation between the number of channel molecules present at the oocyte surface and the current expressed in individual oocyte (43). Complexes comprising α subunits reach the cell surface, though less efficiently for αβ, αγ, and α alone compared with αβγ-injected oocytes, while no signal could be detected on oocytes injected with either β or γ subunits alone. Other studies have revealed that the α subunit plays a role in the trafficking of the channel to the cell surface (42) or in its anchoring to the cytoskeleton (44). A fourth subunit sharing 37% homology with α and 25 to 30% with β and γ subunits has been cloned in human (45). When expressed in the oocyte, it assembles with β and γ subunits like an α subunit and gives rise to sodium currents with slight biophysical differences when compared with the αβαγ channel. The amiloride sensitivity is lower, and selectivity of lithium over sodium is decreased. The delta subunit is mainly expressed in the testis, pancreas, ovary, brain, and heart. By contrast to αβγ subunits found in several species (human, rat, mouse, bovine, chicken, rabbit, chimpanzee, guinea pig, pig, dog, frog), the δ subunit was found only in human and chimpanzee.Figure 1.: Time-course of epithelial sodium channel (EnaC) expression in the Xenopus oocyte system. Oocytes were injected with rENaC αβγ ([Black Lozenge]), αβ (▵), αγ (⋄), βγ (○), or water and were measured by a two-electrode voltage clamp every day. In the upper panel, the maximal relative currents to the wild-type (WT) are expressed. At day 6, P < 0.05 for all the conditions over water-injected oocytes.Structure/Function. In the absence of a three-dimensional structure for DEG/ENaC proteins, site directed mutagenesis provides the best tool to explore structure/function relationships of the channel (see reference 46 for review). In the cytoplasmic N-terminal domain, a highly conserved region preceding the first transmembrane domain is involved in the gating of the channel (47,48). The relative importance of this domain on gating is not similar between subunits (α>>β>γ). Another important feature of the amino-terminal region is the presence of numerous lysine residues. Staub et al. (49) demonstrated that these residues (especially on the γ and α subunits) can be ubiquitinated and are key elements determining the half-life of the channel. Chalfant et al. (50) reported that a motif present on the rat α subunit (KGDK) could play a role in regulating the endocytosis of the channel. Finally, the N-terminal domain was reported to be involved in channel assembly as demonstrated for the γ subunit (51). The extracellular loop is the largest domain of the protein, encoded by ten different exons, in comparison with the N- or the C-terminus which are each encoded by one exon. It contains several glycosylation sites (52,53). Two cysteine-rich boxes (CRB1 and CRB2) are also present in the loop. CRB1 contains six cysteines and CRB2 ten cysteines. Firsov et al. (54) demonstrated that interaction between cysteines 1 and 6 in the first CRB and cysteines 11 and 12 in the second CRB are critical for channel trafficking to the cell membrane. Using antiamiloride antibodies, Ismailov et al. (55) identified an amiloride binding site in the extracellular loop, but its functional relevance is challenged by others (56). Waldmann et al. (57) and Schild et al. (58) highlighted the importance of the pre-M2 domain in the amiloride block and the selectivity filter. Schild et al. (58) found point mutations that substantially affect the amiloride sensitivity on the three subunits. Kellenberger et al. (56,59) recently solved the molecular aspects of the selectivity filter and proposed a model of the external pore of the channel. The intracellular carboxy-terminus contains several functional domains involved in the regulation of the number of channels present at the cell surface. A PPPxY motif is present on all three ENaC subunits, but curiously not on the δ subunit. Deletion or missense mutation of this motif on the β and γ subunits are found in patients affected by the Liddle syndrome, underscoring its importance in channel regulation (60–64). In Liddle syndrome, the channel is hyperactive because of two factors: an increased number of channels present at the cell surface and an increased intrinsic activity of ENaC. Staub et al. (65) demonstrated that the so-called PY motif is the target of Nedd4, a ubiquitin-protein ligase, which binds to the PY motif through its WW domains. The binding allows the ubiquitination of ENaC and its degradation. In Liddle syndrome, this interaction between Nedd4 and the PY motif of the β and γ subunits is no longer possible, and this leads to a higher number of hyperactive channels at the cell surface (see reference 66 for review). An alternative explanation for the regulation of the number of channels present at the cell surface was pointed out by Shimkets et al. (67). They propose that the PY motif plays a role as endocytic signal. Another possibility of ENaC regulation is phosphorylation. Serines and threonines, but not tyrosines, were found to be phosporylated on the C-termini of β and γ subunits in the basal state, when channel subunits were stably expressed in MDCK cells (68). In these cells, aldosterone and insulin increased basal phosphorylation of the β and γ subunits, but not the α subunit. However, the phosphorylated residues are not yet identified and the functional relevance not established. Finally, a proline rich domain in the C-terminus of the α subunit that resembles a SH3 protein-protein interaction domain was involved in the interaction with an element of the cytoskeleton, α-spectrin (44). This interaction could play a role in the localization and/or anchoring of the channel at the cell surface. Tissue- and Cell-Specific Expression of ENaC. All three subunits are expressed in the main aldosterone-sensitive target cells or tissues, namely the last part of the nephron in the kidney (69–72), in the distal colon, in the ducts of salivary and sweat glands (69), and in the lung, where they could be expressed differentially along the pulmonary tree (73–77). However, in some tissues, only one or two subunits are expressed, leading to speculations concerning the stoechiometry of the channel and their physiologic function. In the thyroid, the α subunit alone is apparently expressed, as well as in the liver and the pancreas. In the eye, the α subunit was found in different cells, but its function remains unknown (78–80). In the colon, the α subunit is present alone as long as aldosterone concentrations are low and β and γ subunits are induced under low-salt diet (81,82). The β subunit is expressed in the placenta (33). β and γ subunits are present in baroreceptor nerve endings (83), the rat foot pad (84), in skin sensory corpuscules (84), and in the urinary bladder of the rat (85,86), where they could play a role in mechanosensation. In the skin, all three subunits are expressed in keratinocytes and hair follicles (87). A recent report showed no sodium transport through cultured human keratinocytes (88,89). These authors and others (90) suggest that ENaC might be involved in cell differentiation in the skin. ENaC Regulation. ENaC is regulated by intracellular as well as by extracellular signaling pathways. Hormones like aldosterone, vasopressin, insulin, or glucocorticoids regulate ENaC expression and/or activity by intracellular signaling cascades (see references 15 and 31 for review). A high intracellular concentration of sodium inhibits ENaC by a feedback mechanism (91). This regulation is defective in Liddle mutants expressed in the Xenopus oocyte (92,93), but this is still poorly understood. A low intracellular pH has a direct inhibitory effect, as demonstrated by the cut-open method on oocytes (91). Several kinases have been implicated in the regulation of ENaC (31). In particular, the aldosterone-induced sgk-kinase was shown to increase ENaC activity and the number of channels present at the cell surface (94–97); this effect is mediated by the phosphorylation of Nedd4–2 (98). Cytoskeleton elements could also play a role in regulating ENaC function. A-spectrin (44), actin (99), and syntaxins (100,101) were reported to influence ENaC function. Luminal high sodium concentrations have been described to downregulate ENaC by self-inhibition (102). Extracellular serine proteases (trypsin and the channel-activating protease [CAP-1]) activate ENaC by an extracellular signaling pathway (103–105), but the molecular mechanisms of their effect have not yet been elucidated. ENaC and Sodium Balance in Human Monogenic Diseases. The cloning of ENaC led to the discovery that a hereditary monogenic form of hypertension, namely the Liddle syndrome, was caused by mutations deleting the PY motif present in the C-terminus of the β- or the γ-ENaC subunits (60–62). Soon after, a salt-wasting syndrome in infancy, PHA-1, was also demonstrated to be caused by genetic defects in the three genes coding for the ENaC subunit (106). This emphasized the importance of ENaC in salt homeostasis and demonstrated that either gain-of-function or loss-of-function mutations could arise on the same genes and lead to mirror phenotypes. Implication of ENaC in tight regulation of salt homeostasis, control of extracellular volume, and BP has opened a new field of investigation and pointed out ENaC and all its regulating factors as candidate proteins potentially involved in salt sensitivity and salt resistance (107). Pseudohypoaldosteronism Type 1 Renal Type 1 PHA Autosomal dominant pattern of inheritance is associated with a renal phenotype characterized by salt-wasting, hyperkalemia, hyponatremia, and metabolic acidosis. It has a mild course, and spontaneous remissions are observed over time (108). Geller et al. (109) studied five of such kindreds and found four mutations in the gene coding for the mineralocorticoid receptor (hMR), introducing frameshift, premature stop codon, or splice donor site deletion, all probably leading to a dysfunctioning mineralocorticoid receptor. Another group found a missense mutation in a family with autosomal dominant PHA-1 (110). This heterozygous L924P mutation leads to a complete abolition of the MR function. Viemann et al. (111) found an insertion (Ins2871C, codon 958) in a sporadic form of renal PHA-1, leading to a frameshift from codon 958 to stop codon 1012 (on 984 amino acid residues for the wild-type protein). Interestingly, one mutation described by Geller et al. and the mutation of Viemann are de novo mutations, suggesting that sporadic cases could be present in the trait. More striking is the fact that only one mutated allele of the mineralocorticoid receptor is sufficient to lead to the renal phenotype. By contrast, heterozygous knockout mice for the mineralocorticoid receptor (MR+/−) grew and bred normally (112). Only homozygous knockout mice (MR−/−) display a renal phenotype with a severe salt wasting, dehydration, and a rapid death about 10 d after birth. Such severe phenotype is not observed in humans, often asymptomatic at birth. These MR−/− mice could be rescued by subcutaneous salt injection until the animals had reached a body mass of 8.5 g (113). Most of these animals survive with this regimen and cope with their defect. This indicates that, as in humans, survival is possible after the first neonatal critical times, where the kidney is too immature to handle sodium and where NaCl supply in milk feeding is insufficient to compensate the renal losses. In that respect, differences in maturation of the kidney in the neonatal period between human and mice could explain the observed species differences. Systemic Type 1 PHA The form of type I PHA inherited as an autosomal recessive mode is characterized by a renal phenotype as in the renal autosomal dominant form. However, no spontaneous remission is observed over time. In addition, other organs than kidneys present defects in salt reabsorption, and this is the reason why this form is called systemic. Lung abnormalities were described as recurrent respiratory infections within weeks or months after birth, which are characterized by cough, tachypnea, fever, and wheezing (114–119). Cultures are sometimes negative, but CMV, RSV, and S. aureus, H. influenzae, S. pneumonia, M. catarrhalis, and even P. aeroginosa were isolated in others. Kerem et al. (118) measured the volume of the airway surface liquid in PHA-1 patients and found an increased volume of more than twice the normal. They hypothesized that the liquid could narrow airways lumen and/or dilute surface-active materials that stabilize small airways, thus explaining the phenotype. The excess of liquid in the airways of these patients results from an absence of electrogenic sodium transport as demonstrated by assessment of the nasal transepithelial voltage difference. Interestingly, no neonatal respiratory abnormality was associated with this form of PHA-I. All PHA-1 patients are born with normal Apgar score. A case of respiratory distress syndrome has been associated to pseudohypoaldosteronism (120). However, some features of this case are incompatible with an EnaC-related PHA-1. First, the patient was a premature, and it is well established that premature infants are more susceptible to develop respiratory distress syndrome without a genetic defect (121). Second, he responded well and quickly to a mineralocorticoid treatment, which is an exclusion criteria for PHA. Finally, systemic phenotype and putative consanguinity of the parents were unfortunately not reported. The genotype was not tested. Prince et al. (122) measured the nasal transepithelial voltage difference in a child affected by PHA-1. They found a basal value of zero and the absence of an amiloride-sensitive voltage. No mutations were found on genes coding for ENaC, but the patient is clearly affected by the systemic form of PHA-1. Other phenotypes in systemic PHA could result from ENaC expression in other tissues. These include gallbladder, where cholelithiasis was described (123,124), Meibomian glands (1), skin (125,126), and placenta with association with polyhydramnios (127–129). Only cases reported with skin or Meibomian glands phenotypes were clearly associated with the systemic form of PHA-1. The relevance of other findings and their link with the syndrome are not yet clear. On the other hand, expression of ENaC in tissues like inner ear or thymus suggest that other clinical phenotypes may have to be unraveled (possibly deafness or immunologic disorder). One might also expect some phenotypic expression of long-term exposure to high plasma aldosterone in the absence of hypertension. High plasma aldosterone has been associated with cardiac fibrosis, but it is unclear whether this relates to the toxic effect of aldosterone or to high BP per se, which commonly accompanies aldosteronism. ENaC Mutations and the Systemic Type I PHA Systemic PHA-1 was linked to chromosome 12p and 16p in human (130). Chang et al. (106) identified three homozygous mutations in five kindreds from Near-East origin (Table 2). All subjects were issued from consanguineous unions and have all the characteristics of the systemic PHA-1. Deletion of 2 bp on the α subunit led to a frameshift at position I68 (αI68fs). A premature stop codon in the extracellular loop of the α subunit predicts a truncated α lacking the second transmembrane domain and the intracellular C-terminus (αR508x). A missense mutation in a highly conserved domain in the intracellular N-terminus of the β subunit (βG37S) reveals genetic heterogeneity of systemic PHA-I. Heterogeneity was reinforced by the report of a splice-site mutation on the γ subunit, leading to abnormal splicing that resulted either in a truncated γ protein or into the replacement of 3 conserved amino acid residues by a novel one (131). Other mutations were since described by different groups (see Table 2). Most of them are on the α subunit, thus illustrating the importance of this subunit in the function of ENaC. By contrast, activating mutations of the Liddle syndrome were found only in the C-terminal part of the β and γ subunits.Table 2: Reported human ENaC mutations causing the autosomal recessive form of PHA-1Compound heterozygous mutations on the genes coding for the ENaC subunits were reported in PHA-1 patients, adding more complexity in the analysis of the trait (118,119). In particular, these PHA-1 patients can present not only autosomal recessive inheritance, but can also appear as sporadic cases. This is the reason why we prefer to name the form associated to ENaC as the systemic form and not the autosomal recessive one. Other groups also reported polymorphisms on the genes coding for ENaC and suggested that they could be related to type I PHA (132,133), especially if associated with polymorphisms present in the gene coding for the mineralocorticoid receptor. Polymorphisms on ENaC that do not lead to a loss-of-function per se, but only when associated with polymorphisms on