Alternative titles; symbols
HGNC Approved Gene Symbol: SCNN1B
SNOMEDCT: 707747007;
Cytogenetic location: 16p12.2 Genomic coordinates (GRCh38): 16:23,278,231-23,381,294 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.2 | Bronchiectasis with or without elevated sweat chloride 1 | 211400 | Autosomal dominant | 3 |
| Liddle syndrome 1 | 177200 | Autosomal dominant | 3 | |
| Pseudohypoaldosteronism, type IB2, autosomal recessive | 620125 | Autosomal recessive | 3 |
Canessa et al. (1993) cloned and characterized subunits of a rat epithelial sodium channel (ENaC) having the functional properties of the distal renal sodium channel, i.e., high sodium selectivity, low conductance, and amiloride sensitivity. The functional channel is composed of at least 3 subunits, alpha (SCNN1A; 600228), beta (SCNN1B), and gamma (SCNN1G; 600761). The 3 subunits show sequence similarities to one another, indicating descent from a common ancestral gene. Each encodes a protein containing 2 transmembrane domains, with intracellular amino and carboxyl termini.
Voilley et al. (1995) cloned the human beta cDNA from a human lung library. The predicted protein is 640 amino acids long and 82% identical to the rat protein.
Shimkets et al. (1994) mapped the SCNN1B gene to human chromosome 16 by use of a somatic cell hybrid panel. This localization was confirmed and refined by linkage analysis in CEPH reference pedigrees showing strong linkage to a cluster of pericentric markers on 16p, with a pairwise lod score of 15.3 with D16S420 at a recombination fraction of zero. Multipoint analysis demonstrated that the gene lies in the interval defined by flanking markers D16S412 and D16S401.
By in situ hybridization and hybridization to pulsed-field gels, Voilley et al. (1995) showed that the beta and gamma genes are located within a common 400-kb fragment on chromosome 16p13-p12.
Pathak et al. (1996) reported that the mouse homolog, Scnn1b, maps to mouse chromosome 7 and that it cosegregates with the mouse Scnn1g and Pkcb (176970) genes.
Canessa et al. (1994) found that the alpha subunit supports sodium conductance when expressed alone; the beta and gamma subunits do not support sodium conductance by themselves, but greatly augment the channel activity when expressed in conjunction with the alpha subunit.
To analyze in detail the properties of the epithelial amiloride-sensitive sodium channel and the functional consequences of mutations causing Liddle syndrome (177200), Firsov et al. (1996) developed a quantitative assay based on the binding of radioiodinated monoclonal antibodies directed against a reporter epitope introduced into the extracellular loop of each of the alpha, beta, and gamma ENaC subunits. Insertion of the epitope into the ENaC sequences did not change its functional and pharmacologic properties. The binding specificity and affinity allowed Firsov et al. (1996) to correlate in individual Xenopus oocytes the macroscopic sodium current with the number of ENaC wildtype and mutant subunits expressed at the cell surface. These experiments demonstrated that (1) only heteromultimeric channels made of alpha, beta, and gamma subunits are maximally and efficiently expressed at the cell surface; (2) the overall ENaC open probability is one order of magnitude lower than previously observed in single-channel recordings; and (3) the R564X mutation (600760.0001) causing Liddle syndrome-1 enhances channel activity by 2 mechanisms, i.e., by increasing ENaC cell surface expression and by changing channel open probability.
Kellenberger et al. (1998) showed that wildtype ENaC is downregulated by intracellular Na+, and that Liddle syndrome mutants decreased the channel sensitivity to inhibition by intracellular Na+. As a result, at high intracellular Na+ activity, there was a 1.2- to 2.4-fold higher cell surface expression and a 2.8- to 3.5-fold higher average current per channel observed in Liddle mutants compared with the wildtype. In addition, Kellenberger et al. (1998) showed that a rapid increase in the intracellular Na+ activity induced downregulation of the activity of wildtype ENaC, but not that of Liddle mutants, on a time scale of minutes, which was directly correlated to the magnitude of the Na+ influx into oocytes. Feedback inhibition of ENaC by intracellular Na+ likely represents an important cellular mechanism for controlling Na+ reabsorption in the distal nephron.
In Xenopus oocyte studies, Abriel et al. (1999) demonstrated that overexpression of wildtype NEDD4 (602278) together with ENaC inhibited activity of the channel. These effects were dependent on the presence of C-terminal PY motifs of ENaC, and changes in channel activity were due entirely to alterations in ENaC numbers at the plasma membrane. Abriel et al. (1999) concluded that NEDD4 is a negative regulator of SCNN1 and suggested that loss of NEDD4 binding sites in ENaC observed in Liddle syndrome might explain the increase in channel number at the cell surface, increased sodium resorption by the distal nephron, and hence hypertension in that disorder.
Snyder (2000) presented results of studies with Fischer rat thyroid cells suggesting that cAMP stimulates sodium ion absorption in part by increasing translocation of ENaC to the cell surface. Stimulation of ENaC by cAMP was dependent on a 5-amino acid sequence (PPPXY) in the C terminus of each subunit. This sequence is the target for mutations that cause Liddle syndrome, suggesting that cAMP-mediated translocation of ENaC to the cell surface is defective in this genetic form of hypertension.
Using Far-Western assays, Harvey et al. (2001) demonstrated that all 3 ENaC subunits bind with strong affinity to the WW domains of NEDD4 and KIAA0439 (NEDD4L; 606384).
Liddle Syndrome 1
In studies of the kindred with Liddle syndrome (LIDLS1; 177200) originally described by Liddle et al. (1963), Shimkets et al. (1994) demonstrated complete linkage of the disorder to the gene encoding the beta subunit of the renal epithelial sodium channel. Analysis of the SCNN1B gene revealed a premature stop codon that truncated the cytoplasmic carboxyl terminus of the encoded protein in affected subjects from Liddle's original kindred (600760.0001). Analysis of subjects with the disorder from 4 additional kindreds demonstrated either premature termination or frameshift mutations in this same carboxy-terminal domain.
In an African American mother and 2 children (kindred K242) with Liddle syndrome, Hansson et al. (1995) identified heterozygosity for a missense mutation in the SCNN1B gene (P616L; 600760.0002) that segregated with disease in the family and was not found in controls. Haplotype analysis revealed that the mutation arose de novo in the mother.
In 4 affected sibs and the affected son of 1 of the sibs from a Japanese family with Liddle syndrome, Tamura et al. (1996) identified heterozygosity for a missense mutation in the SCNN1B gene (Y618H; 600760.0004) that segregated with disease.
In a large kindred with Liddle syndrome, Findling et al. (1997) identified a heterozygous 1-bp insertion in the SCNN1B gene (600760.0005) that segregated fully with disease and was not found in more than 750 controls.
In a mother and 3 sons with Liddle syndrome, Jeunemaitre et al. (1997) identified heterozygosity for a 32-bp deletion in SCNN1B (600760.0006).
In affected members from a 3-generation Japanese family with Liddle syndrome, Inoue et al. (1998) identified heterozygosity for a missense mutation in the SCNN1B gene (P615S; 600760.0007).
In a Japanese mother and daughter with Liddle syndrome, Furuhashi et al. (2005) identified heterozygosity for a missense mutation in SCNN1B (P616R; 600760.0008).
Pseudohypoaldosteronism, Type 1B2, Autosomal Recessive
Mutations resulting in constitutive activation of epithelial sodium channel activity have been demonstrated in the beta and gamma subunits as the cause of the autosomal dominant form of hypertension, Liddle syndrome, which is characterized by volume expansion, hypokalemia, and alkalosis. This finding raised the possibility that mutations causing loss of epithelial sodium channel activity could cause the converse phenotype of volume depletion, hyperkalemia and acidosis characteristic of patients with pseudohypoaldosteronism type I. Chang et al. (1996) found that such is indeed the case; they identified 2 mutations in the alpha subunit (SCNN1A; 600228.0001-600228.0002) and 1 in the beta subunit (SCNN1B; 600760.0003) in kindreds with PHA1B1 (264350) and PHA1B2 (620125), respectively.
In a boy (patient 14) with PHA1B2, Saxena et al. (2002) identified a homozygous splice site mutation in the SCNN1B gene (600760.0016). The mutation, which was identified by whole-genome sequencing, was present in heterozygous state in the parents.
By sequence analysis of the ENaC subunit genes in a 4-year-old Israeli-Arab boy with multisystem PHA, Edelheit et al. (2005) identified the same homozygous splice site mutation in the SCNN1B gene (600760.0016) that had been identified by Saxena et al. (2002). The parents were heterozygous for the mutation.
By direct sequencing of the ENaC subunit genes in a 3.5-year-old Turkish boy with pseudohypoaldosteronism, Dogan et al. (2012) identified a homozygous splice site mutation in intron 8 of the SCNN1B gene (600760.0017). The parents were heterozygous for the mutation.
Cayir et al. (2019) performed next-generation sequencing on a 6-month-old Turkish boy with PHA and identified compound heterozygous mutations in the SCNN1B gene, a nonsense mutation (Y29X; 600760.0018) inherited from his mother and a splice site mutation (600760.0019) inherited from his father.
Bronchiectasis with or without Elevated Sweat Chloride 1
In 2 patients with elevated sweat chloride and pulmonary disease but normal pancreatic exocrine function (BESC1; 211400), who were negative for mutation in the CFTR gene (602421), Sheridan et al. (2005) identified compound heterozygosity for mutations in the SCNN1B gene (600760.0009-600760.0012, respectively). Although 1 of the patients had an episode of hyponatremic dehydration with elevated aldosterone and renin at 6 months of age, at the time of study both patients had normal salivary, serum, and urine electrolytes, normal serum aldosterone and renin activity, and normal blood pressure. Sheridan et al. (2005) concluded that deleterious SCNN1B mutations can produce symptoms in the lungs and sweat glands without the renal features of PHA1 or Liddle syndrome.
Fajac et al. (2008) screened the SCNN1B gene in 55 patients with idiopathic bronchiectasis who had one or no CFTR mutations and identified heterozygosity for 3 missense mutations in SCNN1B in 5 patients, 2 of whom carried no CFTR mutation (600760.0013-600760.0015, respectively). Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene.
Pradervand et al. (1999) inserted a stop codon, corresponding to residue arg566 in the human, into the mouse Scnn1b gene. Heterozygous mice therefore had a mutation homologous to that found in the original pedigree described by Liddle et al. (1963) (see 600760.0001). Pradervand et al. (1999) reported that on a normal salt diet, mice heterozygous and homozygous for the Liddle mutation developed normally during the first 3 months of life. In these mice, blood pressure was not different from wildtype despite evidence for increased sodium reabsorption in distal colon and low plasma aldosterone, suggesting chronic hypervolemia. On a high salt intake, the Liddle mice developed high blood pressure, metabolic alkalosis, and hypokalemia accompanied by cardiac and renal hypertrophy. This animal model reproduced to a large extent a human form of salt-sensitive hypertension.
To test the hypothesis that accelerated sodium transport can produce lung disease similar to that seen in cystic fibrosis (219700), Mall et al. (2004) generated mice with airway-specific overexpression of epithelial sodium channels. Mall et al. (2004) used the airway-specific club cell secretory protein promoter to target expression of individual SCNN1 subunit transgenes to lower airway epithelia. They demonstrated that increased airway sodium absorption in vivo caused airway surface liquid volume depletion, increased mucus concentration, delayed mucus transport, and mucus adhesion to airway surfaces. Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation, and poor bacterial clearance. Mall et al. (2004) concluded that increasing airway sodium absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease.
After demonstrating complete linkage between the SCNN1B gene and Liddle syndrome (LIDLS1; 177200) in the pedigree originally described by Liddle et al. (1963), Shimkets et al. (1994) identified a causative premature stop codon in the SCNN1B gene. A C-to-T transition at the first nucleotide of codon 564 resulted in the stop codon and deletion of the last 75 amino acids from the encoded protein (arg564 to ter; R564X). This truncation left the second transmembrane domain intact but removed virtually the entire cytoplasmic carboxyl tail of the protein.
Hansson et al. (1995) described an African American kindred (K242) with Liddle syndrome (LIDLS1; 177200) in which an affected mother and 2 children had a mutation in codon 616 of the SCNN1B gene resulting in the substitution of leucine for one of the highly conserved proline residues present in the C terminus (P616L). The mutation segregated fully with disease in the family and was not found in 1,000 controls; haplotype analysis demonstrated that the mutation arose de novo in the mother. All previously reported mutations had deletion of the last 45 to 76 normal amino acids from the cytoplasmic C terminus of either the beta or the gamma subunit; these segments are similar to the SH3-binding domains that mediate protein-protein interaction. The functional significance of the P616L mutation was indicated by the concordance between Liddle syndrome and the mutation and by the marked activation of amiloride-sensitive sodium channel activity seen in Xenopus oocytes expressing channels containing this mutant subunit.
In an Arab kindred (PHA K8) living in Israel with at least 5 cases of type I pseudohypoaldosteronism (PHA1B2; 620125) in 2 different sibships, Chang et al. (1996) identified a gly37-to-ser (G37S) substitution in the beta subunit of the epithelial sodium channel. The affected individuals were homozygous for the mutation. Genotypes of marker loci tightly linked to SCNN1B were all homozygous in the affected subjects but not their unaffected relatives, strongly supporting the identity by descent of the observed mutation. Gly37 is in a segment that shows homology among all members of the extended epithelial sodium channel family, ranging from humans to C. elegans. Thus, this is another example of both activating and inactivating mutations of a given gene leading to different disorders.
Grunder et al. (1997) investigated the mechanism of channel inactivation by the G37S mutation. Homologous mutations, introduced into alpha, beta, or gamma subunits, all significantly reduced macroscopic sodium channel currents recorded in Xenopus laevis oocytes microinjected with mutant RNA. No significant difference in surface expression of mutant compared to wildtype channels was demonstrated by quantitative studies of the number of channel molecules. Furthermore, single-channel conductances and ion selectivities of the mutant channels were identical to those of wildtype. These results suggested that the decrease in macroscopic sodium currents was due to a decrease in channel open probability, indicating that mutations of a conserved glycine in the N terminus of ENaC subunits change ENaC channel gating, thus explaining the pathophysiology of the disorder. Single-channel recordings of channels containing the mutant alpha subunit (alpha-G95S) directly demonstrated a striking reduction in channel open probability. Grunder et al. (1997) proposed that the G37S mutation favors a gating mode characterized by short-open and long-closed times.
In 4 affected sibs and the affected son of 1 of the sibs from a Japanese family with hypertension, hypokalemia, and suppressed aldosterone secretion (LIDLS1; 177200), originally reported by Matsui et al. (1976), Tamura et al. (1996) found a tyr618-to-his (Y618H) mutation 2 bp downstream from the P616L missense mutation (600760.0002). Functional expression studies in Xenopus oocytes revealed constitutive activation of the Y618H mutant indistinguishable from that observed for the R564X deletion mutant (600760.0001) identified in the original pedigree reported by Liddle et al. (1963). The authors stated that the region between pro616 and tyr618 appears to be critically important for regulation of epithelial sodium channel activity.
Findling et al. (1997) described a kindred (K176) with clinical features of mild hypertension and decreased aldosterone secretion. A frameshift mutation in the C terminus of SCNN1B was identified in the index case to establish the diagnosis of Liddle syndrome (LIDLS1; 177200). This mutation inserts an additional cytosine residue at codon 592, changing the encoded protein from amino acid 593 onward and causing a new termination at codon 605. This frameshift removes the last 45 amino acids of the normal protein, including the proline-rich target. This mutation was not found on over 1,500 chromosomes from unrelated subjects, indicating that it is rare in the population.
Jeunemaitre et al. (1997) demonstrated heterozygosity for a deletion in the SCNN1B gene in a mother and her 3 sons with Liddle syndrome (LIDLS1; 177200). The mutation was a deletion of 32 bp that had modified the open reading frame and introduced a stop codon at position 582. The 4 affected members of the family had early-onset and moderate to severe hypertension. Mild hypokalemia and suppressed levels of plasma renin and aldosterone were observed in all affected subjects. Administration of 10 mg/day amiloride for 2 months normalized the blood pressure and plasma potassium levels of all 4 subjects, whereas plasma and urinary aldosterone levels remained low. A similar pattern was observed after 11 years of follow-up. Many of the mother's relatives had had stroke or sudden death before age 60 years.
Inoue et al. (1998) sequenced the C termini of the beta and gamma subunits of the epithelial sodium channel in a Japanese family clinically diagnosed as having Liddle syndrome (LIDLS1; 177200) and found a pro615-to-ser (P615S) missense mutation in the PY motif of the beta subunit. Expression studies of the mutant in Xenopus oocytes resulted in an approximately 3-fold increase in the amiloride-sensitive sodium current compared to the wildtype (p = 0.001). The authors concluded that these findings support the hypothesis that a conserved PPPXY sequence (PY motif) of the C terminus of the alpha, beta, or gamma subunits is involved in the regulation of the channel activity.
In a Japanese mother and daughter with Liddle syndrome (LIDLS1; 177200), Furuhashi et al. (2005) found a C-to-G transversion in exon 13 of the SCNN1B gene that resulted in a pro616-to-arg (P616R) amino acid substitution in the PY motif of beta-ENaC. Functional studies using the P616R mutant expressed in Xenopus oocytes showed an approximately 6-fold increase in the amiloride-sensitive sodium channel activity compared with that of the wildtype. These findings provide additional clinical evidence that a conserved PY motif is critically important for the regulation of ENaC activity.
In a 23-year-old African American woman (patient 824) with elevated sweat chloride and pulmonary disease with a forced expiratory volume in 1 second (FEV1) that was 73% of predicted (BESC1; 211400), who was negative for mutation in the CFTR gene (602421), Sheridan et al. (2005) identified compound heterozygosity for a 1670-2A-G transition (600760.0010) at a highly conserved nucleotide in intron 12 of the SCNN1B gene, and a pro267-to-leu (P267L) substitution at a conserved residue in the SCNN1B gene. The patient's mother was shown to carry the splice site mutation; her father was not available for analysis. RT-PCR of nasal epithelial RNA from the patient revealed that the splice site mutation results in aberrant splicing and generation of 2 stable SCNN1B transcripts with substantial alterations in sequence. The first transcript retains 83 nucleotides from the 3-prime end of intron 12 and is predicted to result in frameshift and termination following the insertion of 188 novel residues. The second transcript lacks the first 33 nucleotides of exon 13, resulting in deletion of 11 amino acids that precede the second transmembrane domain. Studies in Xenopus oocytes showed that the P267L mutant was associated with sodium currents that were significantly reduced compared to wildtype (p = 0.002). The P267L mutation was not found in 256 ethnically matched control alleles.
For discussion of the splice site mutation in the SCNN1B gene (1670-2A-G) that was found in compound heterozygous state in a patient with bronchiectasis with elevated sweat chloride (BESC1; 211400) by Sheridan et al. (2005), see 600760.0009.
In a 7-year-old Caucasian boy (patient 828) with elevated sweat chloride and severe pulmonary disease with a forced expiratory volume in 1 second (FEV1) that was 24% of predicted (BESC1; 211400), who was negative for mutation in the CFTR gene (602421), Sheridan et al. (2005) identified compound heterozygosity for a gly294-to-ser (G294S) and a glu539-to-lys (E539K; 600760.0012) substitution at conserved residues in the SCNN1B gene. Each parent was shown to carry one of the mutations. Studies in Xenopus oocytes showed that the G294S mutant was associated with sodium currents that were significantly higher than those of wildtype (p = 0.004), whereas the E539K mutant was associated with sodium currents that were significantly lower than wildtype (p less than 0.001). At age 6 months, the boy had an episode of dehydration associated with transient elevation of aldosterone and renin levels, but otherwise had normal aldosterone and renin levels. The G294S and E539K mutations were not found in 324 and 254 ethnically matched control alleles, respectively.
For discussion of the glu539-to-lys (E539K) mutation in the SCNN1B gene that was found in compound heterozygous state in a patient with bronchiectasis with elevated sweat chloride (BESC1; 211400) by Sheridan et al. (2005), see 600760.0011.
In a 35-year-old woman with idiopathic bronchiectasis and a normal sweat chloride but abnormal nasal potential difference (BESC1; 211400), who was negative for mutation in the CFTR gene (602421), Fajac et al. (2008) identified heterozygosity for a 1105C-A transversion in exon 7 of the SCNN1B gene, resulting in a pro369-to-thr (P369T) substitution. The mutation was not found in 50 ethnically matched controls. The patient had a forced expiratory volume in 1 second (FEV1) that was 86% of predicted.
In a 60-year-old woman with idiopathic bronchiectasis and an abnormal sweat chloride but normal nasal potential difference (BESC1; 211400), who was negative for mutation in the CFTR gene (602421), Fajac et al. (2008) identified heterozygosity for an 863A-G transition in exon 5 of the SCNN1B gene, resulting in an asn288-to-ser (N288S) substitution at a highly conserved residue. The mutation was not found in 50 ethnically matched controls. The patient had a forced expiratory volume in 1 second (FEV1) that was 93% of predicted.
In 3 patients with idiopathic bronchiectasis and normal nasal potential differences, 2 of whom had abnormal sweat chlorides (BESC1; 211400), Fajac et al. (2008) identified heterozygosity for a 245C-G transversion in exon 2 of the SCNN1B gene, resulting in a ser82-to-cys (S82C) substitution at a highly conserved residue. All 3 patients also carried 1 mutation in the CFTR gene: F508del (602421.0001) in 1 patient and the 5T variant (602421.0086) in the other 2 patients. Forced expiratory volumes (FEV1s) in these 3 patients ranged between 77% and 89% of predicted. The S82C mutation, which had been previously described by Sheridan et al. (2005), was not found in 50 ethnically matched controls or in a 'control' population of 56 cystic fibrosis (219700) patients with 2 pathogenic CFTR mutations.
In a boy (patient 14) with autosomal recessive pseudohypoaldosteronism type IB2 (PHA1B2; 620125), Saxena et al. (2002) sequenced the SCNN1B gene and identified a homozygous splice site mutation (c.1699+1G-A) in exon 12 of the SCNN1B gene. The mutation, which was identified by whole-genome sequencing, was present in heterozygous state in the parents. The mutation changes the conserved GT sequence at the 5-prime end, preventing correct splicing of the mRNA and resulting in the absence of a functional beta subunit in the epithelial sodium channel.
Edelheit et al. (2005) identified homozygosity for the c.1699+1G-A mutation in intron 12 of the SCNN1B gene in a 4-year-old Israeli Arab boy (patient 66) with PHA1B2. The mutation was present in heterozygous state in the parents. Edelheit et al. (2005) noted that the mutation occurs at a CpG hotspot and does not necessarily indicate a common genetic origin for the mutations.
By sequencing of the ENaC subunit genes in a 3.5-year-old Turkish boy with type IB2 pseudohypoaldosteronism (PHA1B2; 620125), Dogan et al. (2012) identified homozygosity for a splice site mutation (c.1266-1G-C) in intron 8 of the SCNN1B gene. The parents were heterozygous for the mutation.
By next-generation sequencing in a 6-month-old Turkish boy with type IB2 pseudohypoaldosteronism (PHA1B2; 620125), Cayir et al. (2019) identified compound heterozygous mutations in the SCNN1B gene: a c.87C-A transition (c.87C-A, NM_000336) in exon 2, resulting in a tyr29-to-ter (Y29X) substitution, and a c.1346+1G-A transition (600760.0019) in intron 9 that likely affects splicing. The mother was heterozygous for the Y29X mutation and the father was heterozygous for the splice site mutation. The Y29X mutation is located in the cytoplasmic topological region (N terminus) of SCNN1B.
For discussion of the c.1346+1G-A transition (c.1346+1G-A, NM_000336) in intron 9 of the SCNNIB gene that was identified in compound heterozygous state in a Turkish boy with pseudohypoaldosteronism type IB2 by Cayir et al. (2019), see 600760.0018.
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