Alternative titles; symbols
HGNC Approved Gene Symbol: SCNN1G
Cytogenetic location: 16p12.2 Genomic coordinates (GRCh38): 16:23,182,745-23,216,883 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.2 | Bronchiectasis with or without elevated sweat chloride 3 | 613071 | Autosomal dominant | 3 |
| Liddle syndrome 2 | 618114 | Autosomal dominant | 3 | |
| Pseudohypoaldosteronism, type IB3, autosomal recessive | 620126 | Autosomal recessive | 3 |
Canessa et al. (1994) reported that the amiloride-sensitive epithelial sodium channel (ENaC), which is expressed in the distal nephron and regulated by aldosterone, is composed of 3 subunits of similar structure: alpha (SCNN1A; 600228), beta (SCNN1B; 600760), and gamma (SCNN1G). Each contains 2 transmembrane spanning domains, intracytoplasmic amino- and carboxy-termini and a cysteine-rich extracellular domain. The 3 proteins share 32 to 37% identity in amino acid sequence. 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.
Voilley et al. (1995) cloned the human SCNN1G cDNA from a human lung library. The predicted protein is 649 amino acids long and 86% identical to the rat protein.
By in situ hybridization and hybridization to pulsed-field gels, Voilley et al. (1995) showed that the SCNN1G and SCNN1B genes are located within a common 400-kb fragment on human chromosome 16p13-p12. The SAH gene (145505), the human homolog of the rat SA gene associated with hypertension, maps to the same region of chromosome 16.
Using a common SSCP variant in the coding region of the SCNN1G gene, Hansson et al. (1995) localized the gene to chromosome 16 and showed 'complete' linkage to the SCNN1B gene. Hansson et al. (1995) demonstrated that the SCNN1G and SCNN1B genes reside on the same YAC clone.
Pathak et al. (1996) reported that the mouse homolog, Scnn1g, maps to mouse chromosome 7 and that it cosegregates with the mouse Scnn1b 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.
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 (177200) might explain the increase in channel number at the cell surface, increased sodium resorption by the distal nephron, and hence hypertension in that disorder.
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).
Volk et al. (2005) found that expression of human ENaC-gamma in a mouse collecting duct cell line increased Na+ transport. Only a small amount of ENaC-gamma was needed to fully increase Na+ transport; further increases in protein expression produced no further increase in Na+ transport. A C-terminally truncated ENaC-gamma protein similar to the ENaC-gamma mutant associated with Liddle syndrome was expressed at lower levels than wildtype ENaC-gamma, but it produced more Na+ transport than the wildtype subunit, supporting the role of the Liddle mutation in producing hypertension.
Thiazolidinediones (TZDs) are PPARG (601487) agonists that sensitize cells to insulin. The use of TZDs to treat type-2 diabetes mellitus (NIDDM; 125853) is complicated by systemic fluid retention. Guan et al. (2005) found that treatment of mice with amiloride, a collecting duct-specific diuretic, reversed the enhanced renal Na+ absorption, edema, and water weight gain caused by TZDs. Deletion of Pparg in mouse collecting duct blocked TZD-induced weight gain, decreased renal Na+ avidity, and increased plasma aldosterone. Treatment of cultured mouse collecting ducts with TZDs increased amiloride-sensitive Na+ absorption and Scnn1g mRNA expression through a Pparg-dependent pathway. Guan et al. (2005) concluded that SCNN1G is a PPARG target gene in the collecting duct and that activation of this pathway mediates fluid retention associated with TZDs.
Liddle Syndrome 2
Constitutive activation of the renal epithelial channel due to mutation in the SCNN1B gene (600761) had been demonstrated to be a cause of Liddle syndrome (see 177200), an autosomal dominant form of hypertension characterized by early onset of hypertension associated with hypokalemia, suppressed plasma renin activity, and suppressed secretion of the mineralocorticoid hormone aldosterone. Hansson et al. (1995) reported a Japanese family (K204) with clinically typical Liddle syndrome (LIDLS2; 618114) and showed that the disorder was caused by mutation in the gamma subunit of the epithelial sodium channel. The mutation introduced a premature termination codon which deleted the last 76 amino acids from the cytoplasmic C terminus of the encoded protein (600761.0001). Expression of the gamma-subunit truncated at this position resulted in activation of channel activities similar to that seen with beta-subunit mutations (e.g., 600760.0001). These findings demonstrated genetic heterogeneity of Liddle syndrome. Moreover, the findings revealed independent roles of the beta and gamma subunits in the negative regulation of channel activity in vivo.
In 3 affected members of a Chinese family with Liddle syndrome-2, Shi et al. (2010) identified a heterozygous nonsense mutation (Q567X; 600761.0007) in the SCNN1G gene.
In a Finnish mother and son with Liddle syndrome, Hiltunen et al. (2002) identified heterozygosity for a missense mutation in the SCNN1G gene (N530S; 600761.0008) that segregated with disease in the family. Functional analysis demonstrated a 2-fold increase in channel activity with the mutant compared to wildtype SCNN1G.
In a Japanese man with Liddle syndrome, Wang et al. (2007) identified heterozygosity for a de novo 5-bp deletion in SCNN1G (600761.0009). The authors stated that this was the first reported sporadic patient with a mutation in the SCNN1G gene, and noted that Liddle syndrome should be considered in patients without a family history of hypertension.
Pseudohypoaldosteronism, Type IB3, Autosomal Recessive
Pseudohypoaldosteronism type I (see PHA1B3, 620126) is an uncommon inherited disorder characterized by salt-wasting and end-organ unresponsiveness to mineralocorticoids. In 3 families with PHA I showing linkage to chromosome 16p, Strautnieks et al. (1996) demonstrated a homozygous mutation in the SCNN1G gene (600761.0002) that resulted in incorrect splicing of the transcript.
Bronchiectasis with or without Elevated Sweat Chloride 3
Fajac et al. (2008) screened the SCNN1G gene in 55 patients with idiopathic bronchiectasis (BESC3; 613071) who had one or no mutations in the CFTR gene (602421) and identified heterozygosity for 2 mutations (G183S, 600761.0005; E197K, 600761.0006), respectively, in 3 patients who lacked mutation in CFTR.
SCNN1G Polymorphisms and Systolic and Pulse Pressure
Iwai et al. (2001) found 4 polymorphisms in the promoter region of the SCNN1G gene, including -173G-A, and confirmed the existence of 2 others in exons 3 and 13. They found that the -173G-A polymorphism had a significant effect on systolic pressure and pulse pressure. The AA genotype was associated with an 11-mm Hg drop in systolic pressure, an 8-mm Hg drop in pulse pressure, and a higher prevalence of hypotension. A transient transfection assay using MDCK cells and human renal epithelial cells indicated that the promoter activity of the -173G allele was higher than that of the -173A allele. The effects of the -173A allele were recessive and the AA genotype was found in just 0.7% of the study population.
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.
In affected members of a Japanese family (K204) with Liddle syndrome (LIDLS2; 618114) mapping to chromosome 16 who did not have a mutation in the SCNN1B gene, Hansson et al. (1995) identified a homozygous G-to-A transition in the last coding exon of the SCNN1G gene, resulting in a trp574-to-ter (W574X) substitution. The protein encoded by this mutant gene contained an intact second transmembrane domain, which is believed to be part of a channel pore, but was truncated 12 amino acids into the cytoplasmic C terminus, deleting the last 76 amino acids from the normal protein. Expression of the mutant protein in Xenopus oocytes displayed increased sodium conductance compared with oocytes expressing wildtype channels. The variant was not found in 1,000 alleles from 500 control subjects of Caucasian, African American, or Asian descent, indicating that it was not a common polymorphism.
In 3 families with autosomal recessive pseudohypoaldosteronism type I showing linkage to 16p (PHA1B3; 620126), Strautnieks et al. (1996) demonstrated a 3-prime splice site mutation (318-1G-A) in the SCNN1G gene. From the nature of abnormal splice products, Strautnieks et al. (1996) proposed that an acceptor splice site mutation immediately upstream from nucleotide 318 had occurred. This would produce 2 abnormal mRNAs, one being the result of skipping the downstream exon and the other resulting from activation of a cryptic splice site 6 bp downstream. This hypothesis was confirmed by finding homozygosity for a G-to-A transition at position -1 of the 3-prime acceptor splice site of intron A for which the parents were both heterozygous. The same mutation was found in 2 other 16p-linked families. Thus Strautnieks et al. (1996) showed that PHA1 is allelic to Liddle syndrome, an autosomal dominant disorder. The Liddle syndrome mutations in SCNN1G and SCNN1B (600760) produce subunits that are truncated at the C terminus. The SCNN1 gene mutation observed in PHA1 was predicted to produce 2 aberrant proteins. One mutant subunit would be grossly truncated in a fashion similar to that described in the alpha-subunit mutations in PHA1. The authors speculated that the mutant subunits may fail to be assembled or, if incorporated, may disrupt the normal multimeric configuration of the channel. The second abnormal gamma-subunit lacks 3 highly conserved amino acids adjacent to the first transmembrane domain. Strautnieks et al. (1996) predicted that this mutation is unlikely to affect the mechanisms mediating hormonal regulation, but may reduce single-channel conductance or open-state probability.
To investigate the molecular basis of 1 sporadic Japanese patient with a systemic form of pseudohypoaldosteronism type I (PHA1B3; 620126), Adachi et al. (2001) determined the nucleotide sequence of the genes of every subunit of the epithelial sodium channel of this patient. The patient was a compound heterozygote for a 1-base deletion in exon 12 (1627delG) and a 1570-1G-A substitution (600761.0004) at the 5-prime splice acceptor site of intron 11 in the gamma subunit gene of the epithelial sodium channel. The 1627delG mutation altered a reading frame, resulting in a premature stop codon in exon 12. Messenger RNA from the allele harboring the splice site mutation was not identified by RT-PCR.
For discussion of the 1570-1G-A substitution at the 5-prime splice acceptor site of intron 11 in the gamma subunit gene of the epithelial sodium channel that was found in compound heterozygous state in a patient with autosomal recessive pseudohypoaldosteronism type I (PHA1B3; 620126) by Adachi et al. (2001), see 600761.0003.
In a 36-year-old woman of African origin with idiopathic bronchiectasis and an abnormal nasal potential difference but normal sweat chloride (BESC3; 613071), who was negative for mutation in the CFTR gene (602421), Fajac et al. (2008) identified heterozygosity for a 547G-A transition in exon 3 of the SCNN1G gene, resulting in a gly183-to-ser (G183S) substitution at a conserved residue. The mutation was not found in 50 Caucasian controls. The patient had a forced expiratory volume in 1 second (FEV1) that was 90% of predicted.
In a 24-year-old Caucasian woman and an unrelated 46-year-old Caucasian male with idiopathic bronchiectasis who had normal sweat chlorides and nasal potential differences (BESC3; 613071) and who were negative for mutation in the CFTR gene (602421), Fajac et al. (2008) identified heterozygosity for a 591G-A transition in exon 3 of the SCNN1G gene, resulting in a glu197-to-lys (E197K) substitution. The mutation was not found in 50 Caucasian controls. The authors noted that both patients were severely affected, with evidence of airway obstruction on pulmonary function tests (FEV1 that was 64% and 35% of predicted, respectively).
In 3 affected members of a Chinese family with Liddle syndrome-2 (LIDLS2; 618114), Shi et al. (2010) identified a heterozygous C-to-T transition in the SCNN1G gene, resulting in a gln567-to-ter (Q567X) substitution.
In a Finnish mother and son with Liddle syndrome (LIDLS2; 618114), Hiltunen et al. (2002) identified heterozygosity for an A-to-G transition 20 nucleotides after the start of exon 13 of the SCNN1G gene, resulting in an asn530-to-ser (N530S) substitution within a conserved sequence of the extracellular loop preceding the second transmembrane domain. The mutation was not found in the proband's unaffected brother or maternal aunt. However, the N530S variant was detected in 1 of 291 healthy Finnish blood donors as well as in 1 of 175 control Finnish men, aged 50 to 69 years, who had low-normal blood pressure; neither individual was available for further evaluation. Functional analysis demonstrated a 2-fold increase in channel activity with the mutant compared to wildtype SCNN1G. Because the N530S mutation did not change single-channel conductance, the authors concluded that the variant increases by 2-fold the channel open probability.
In a Japanese man with hypertension, hypokalemia, and low plasma renin activity (LIDLS2; 618114), Wang et al. (2007) identified heterozygosity for a de novo 5-bp deletion (AGCTC) at codon 583 (NM_001039) in the last exon of the SCNN1G gene, causing a frameshift predicted to result in a premature termination codon at residue 585 with removal of 65 amino acids as well the change of codons E583 and A584 to D583 and P584. The mutation was not found in his unaffected parents or in 50 randomly selected hypertensive patients or 50 normotensive controls.
Abriel, H., Loffing, J., Rebhun, J. F., Pratt, J. H., Schild, L., Horisberger, J.-D., Rotin, D., Staub, O. Defective regulation of the epithelial Na(+) channel by Nedd4 in Liddle's syndrome. J. Clin. Invest. 103: 667-673, 1999. [PubMed: 10074483] [Full Text: https://doi.org/10.1172/JCI5713]
Adachi, M., Tachibana, K., Asakura, Y., Abe, S., Nakae, J., Tajima, T., Fujieda, K. Compound heterozygous mutations in the gamma subunit gene of ENaC (1627delG and 1570-1G-A) in one sporadic Japanese patient with a systemic form of pseudohypoaldosteronism type 1. J. Clin. Endocr. Metab. 86: 9-12, 2001. [PubMed: 11231969] [Full Text: https://doi.org/10.1210/jcem.86.1.7116]
Canessa, C. M., Schild, L., Buell, G., Thorens, B., Gautschi, I., Horisberger, J.-D., Rossier, B. C. Amiloride-sensitive epithelial Na(+)-channel is made of three homologous subunits. Nature 367: 463-467, 1994. [PubMed: 8107805] [Full Text: https://doi.org/10.1038/367463a0]
Fajac, I., Viel, M., Sublemontier, S., Hubert, D., Bienvenu, T. Could a defective epithelial sodium channel lead to bronchiectasis. Respir. Res. 9: 46, 2008. Note: Electronic Article. [PubMed: 18507830] [Full Text: https://doi.org/10.1186/1465-9921-9-46]
Guan, Y., Hao, C., Cha, D. R., Rao, R., Lu, W., Kohan, D. E., Magnuson, M. A., Redha, R., Zhang, Y., Breyer, M. D. Thiazolidinediones expand body fluid volume through PPAR-gamma stimulation of ENaC-mediated renal salt absorption. Nature Med. 11: 861-866, 2005. [PubMed: 16007095] [Full Text: https://doi.org/10.1038/nm1278]
Hansson, J. H., Nelson-Williams, C., Suzuki, H., Schild, L., Shimkets, R., Lu, Y., Canessa, C., Iwasaki, T., Rossier, B., Lifton, R. P. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nature Genet. 11: 76-82, 1995. [PubMed: 7550319] [Full Text: https://doi.org/10.1038/ng0995-76]
Harvey, K. F., Dinudom, A., Cook, D. I., Kumar, S. The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J. Biol. Chem. 276: 8597-8601, 2001. [PubMed: 11244092] [Full Text: https://doi.org/10.1074/jbc.C000906200]
Hiltunen, T. P., Hannila-Handelberg, T., Petajaniemi, N., Kantola, I., Tikkanen, I., Virtamo, J., Gautschi, I., Schild, L., Kontula, K. Liddle's syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel gamma subunit. J. Hypertens. 20: 2383-2390, 2002. [PubMed: 12473862] [Full Text: https://doi.org/10.1097/00004872-200212000-00017]
Iwai, N., Baba, S., Mannami, T., Katsuya, T., Higaki, J., Ogihara, T., Ogata, J. Association of sodium channel gamma-subunit promoter variant with blood pressure. Hypertension 38: 86-89, 2001. [PubMed: 11463765] [Full Text: https://doi.org/10.1161/01.hyp.38.1.86]
Mall, M., Grubb, B. R., Harkema, J. R., O'Neal, W. K., Boucher, R. C. Increased airway epithelial Na(+) absorption produces cystic fibrosis-like lung disease in mice. Nature Med. 10: 487-493, 2004. [PubMed: 15077107] [Full Text: https://doi.org/10.1038/nm1028]
Pathak, B. G., Shaughnessy, J. D., Jr., Meneton, P., Greeb, J., Shull, G. E., Jenkins, N. A., Copeland, N. G. Mouse chromosomal location of three epithelial sodium channel subunit genes and an apical sodium chloride cotransporter gene. Genomics 33: 124-127, 1996. [PubMed: 8617496] [Full Text: https://doi.org/10.1006/geno.1996.0168]
Shi, J., Chen, X., Ren, Y., Long, Y., Tian, H. Liddle's syndrome caused by a novel mutation of the gamma subunit of epithelial sodium channel gene SCNN1G in Chinese. Chin. J. Med. Genet. 27: 132-135, 2010. [PubMed: 20376790] [Full Text: https://doi.org/10.3760/cma.j.issn.1003-9406.2010.02.003]
Strautnieks, S. S., Thompson, R. J., Gardiner, R. M., Chung, E. A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families. Nature Genet. 13: 248-250, 1996. [PubMed: 8640238] [Full Text: https://doi.org/10.1038/ng0696-248]
Voilley, N., Bassilana, F., Mignon, C., Merscher, S., Mattei, M.-G., Carle, G. F., Lazdunski, M., Barbry, P. Cloning, chromosomal localization, and physical linkage of the beta and gamma subunits (SCNN1B and SCNN1G) of the human epithelial amiloride-sensitive sodium channel. Genomics 28: 560-565, 1995. [PubMed: 7490094] [Full Text: https://doi.org/10.1006/geno.1995.1188]
Volk, K. A., Husted, R. F., Sigmund, R. D., Stokes, J. B. Overexpression of the epithelial Na+ channel gamma subunit in collecting duct cells: interactions of Liddle's mutations and steroids on expression and function. J. Biol. Chem. 280: 18348-18354, 2005. [PubMed: 15755736] [Full Text: https://doi.org/10.1074/jbc.M413689200]
Wang, Y., Zheng, Y., Chen, J., Wu, H., Zheng, D., Hui, R. A novel epithelial sodium channel gamma-subunit de novo frameshift mutation leads to Liddle syndrome. Clin. Endocr. 67: 801-804, 2007. [PubMed: 17634077] [Full Text: https://doi.org/10.1111/j.1365-2265.2007.02967.x]