SCNNB_HUMAN
ID SCNNB_HUMAN Reviewed; 640 AA.
AC P51168; C5HTZ2; O60891; Q96KG2; Q9UJ32; Q9UMU5;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 2.
DT 03-AUG-2022, entry version 210.
DE RecName: Full=Amiloride-sensitive sodium channel subunit beta;
DE AltName: Full=Beta-NaCH;
DE AltName: Full=Epithelial Na(+) channel subunit beta;
DE Short=Beta-ENaC;
DE Short=ENaCB;
DE AltName: Full=Nonvoltage-gated sodium channel 1 subunit beta;
DE AltName: Full=SCNEB;
GN Name=SCNN1B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Lung;
RX PubMed=7490094; DOI=10.1006/geno.1995.1188;
RA Voilley N., Bassilana F., Mignon C., Merscher S., Mattei M.-G., Carle G.F.,
RA Lazdunski M., Barbry P.;
RT "Cloning, chromosomal localization, and physical linkage of the beta and
RT gamma subunits (SCNN1B and SCNN1G) of the human epithelial amiloride-
RT sensitive sodium channel.";
RL Genomics 28:560-565(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT PRO-336, FUNCTION,
RP GLYCOSYLATION, AND TISSUE SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=7762608; DOI=10.1152/ajpcell.1995.268.5.c1157;
RA McDonald F.J., Snyder P.M., Price M.P., Welsh M.J.;
RT "Cloning and expression of the beta- and gamma-subunits of the human
RT epithelial sodium channel.";
RL Am. J. Physiol. 268:C1157-C1163(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Epithelium;
RX PubMed=9813171; DOI=10.1006/bbrc.1998.9625;
RA Saxena A., Hanukoglu I., Strautnieks S.S., Thompson R.J., Gardiner R.M.,
RA Hanukoglu A.;
RT "Gene structure of the human amiloride-sensitive epithelial sodium channel
RT beta subunit.";
RL Biochem. Biophys. Res. Commun. 252:208-213(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=12107247; DOI=10.1210/jcem.87.7.8674;
RA Saxena A., Hanukoglu I., Saxena D., Thompson R.J., Gardiner R.M.,
RA Hanukoglu A.;
RT "Novel mutations responsible for autosomal recessive multisystem
RT pseudohypoaldosteronism and sequence variants in epithelial sodium channel
RT alpha-, beta-, and gamma-subunit genes.";
RL J. Clin. Endocrinol. Metab. 87:3344-3350(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, Lung, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] OF 1-259.
RX PubMed=10493829; DOI=10.1006/geno.1999.5927;
RA Loftus B.J., Kim U.-J., Sneddon V.P., Kalush F., Brandon R., Fuhrmann J.,
RA Mason T., Crosby M.L., Barnstead M., Cronin L., Mays A.D., Cao Y., Xu R.X.,
RA Kang H.-L., Mitchell S., Eichler E.E., Harris P.C., Venter J.C.,
RA Adams M.D.;
RT "Genome duplications and other features in 12 Mb of DNA sequence from human
RT chromosome 16p and 16q.";
RL Genomics 60:295-308(1999).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-56 (ISOFORM 2).
RC TISSUE=Kidney;
RA Thomas C.P., Auerbach S.D., Loftus R.W., Li X., Itani O.A.;
RT "Separate promoters of the human epithelial sodium channel beta subunit
RT direct expression of alternate transcripts that encode N-terminal protein
RT variants.";
RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 515-640.
RX PubMed=7954808; DOI=10.1016/0092-8674(94)90250-x;
RA Shimkets R.A., Warnock D.G., Bositis C.M., Nelson-Williams C.,
RA Hansson J.H., Schambelan M., Gill J.R., Ulick S., Milora R.V.,
RA Findling J.W., Canessa C.M., Rossier B.C., Lifton R.P.;
RT "Liddle's syndrome: heritable human hypertension caused by mutations in the
RT beta subunit of the epithelial sodium channel.";
RL Cell 79:407-414(1994).
RN [10]
RP DEFINITION OF DIFFERENT FORMS OF PSEUDOHYPOALDOSTERONISM TYPE 1.
RX PubMed=1939532; DOI=10.1210/jcem-73-5-936;
RA Hanukoglu A.;
RT "Type I pseudohypoaldosteronism includes two clinically and genetically
RT distinct entities with either renal or multiple target organ defects.";
RL J. Clin. Endocrinol. Metab. 73:936-944(1991).
RN [11]
RP SUBUNIT.
RX PubMed=7499195; DOI=10.1074/jbc.270.46.27411;
RA Waldmann R., Champigny G., Bassilana F., Voilley N., Lazdunski M.;
RT "Molecular cloning and functional expression of a novel amiloride-sensitive
RT Na+ channel.";
RL J. Biol. Chem. 270:27411-27414(1995).
RN [12]
RP INTERACTION WITH WWP1 AND WWP2.
RX PubMed=9169421; DOI=10.1074/jbc.272.23.14611;
RA Pirozzi G., McConnell S.J., Uveges A.J., Carter J.M., Sparks A.B.,
RA Kay B.K., Fowlkes D.M.;
RT "Identification of novel human WW domain-containing proteins by cloning of
RT ligand targets.";
RL J. Biol. Chem. 272:14611-14616(1997).
RN [13]
RP INTERACTION WITH NEDD4 AND NEDD4L.
RX PubMed=11244092; DOI=10.1074/jbc.c000906200;
RA Harvey K.F., Dinudom A., Cook D.I., Kumar S.;
RT "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial
RT sodium channel.";
RL J. Biol. Chem. 276:8597-8601(2001).
RN [14]
RP INTERACTION WITH NEDD4 AND WWP2.
RX PubMed=12167593; DOI=10.1152/ajprenal.00080.2002;
RA McDonald F.J., Western A.H., McNeil J.D., Thomas B.C., Olson D.R.,
RA Snyder P.M.;
RT "Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial
RT Na(+) channel.";
RL Am. J. Physiol. 283:F431-F436(2002).
RN [15]
RP SUBUNIT.
RX PubMed=16423824; DOI=10.1074/jbc.m512293200;
RA Ji H.L., Su X.F., Kedar S., Li J., Barbry P., Smith P.R., Matalon S.,
RA Benos D.J.;
RT "Delta-subunit confers novel biophysical features to alpha beta gamma-human
RT epithelial sodium channel (ENaC) via a physical interaction.";
RL J. Biol. Chem. 281:8233-8241(2006).
RN [16]
RP GENOTYPE-PHENOTYPE RELATIONSHIPS IN PHA1B, AND LONG-TERM EFFECTS OF
RP MUTATIONS ON PHA1B.
RX PubMed=18634878; DOI=10.1016/j.jsbmb.2008.06.013;
RA Hanukoglu A., Edelheit O., Shriki Y., Gizewska M., Dascal N., Hanukoglu I.;
RT "Renin-aldosterone response, urinary Na/K ratio and growth in
RT pseudohypoaldosteronism patients with mutations in epithelial sodium
RT channel (ENaC) subunit genes.";
RL J. Steroid Biochem. Mol. Biol. 111:268-274(2008).
RN [17]
RP INVOLVEMENT IN PSEUDOHYPOALDOSTERONISM TYPE 1.
RX PubMed=20064610; DOI=10.1016/j.jsbmb.2010.01.002;
RA Edelheit O., Hanukoglu I., Shriki Y., Tfilin M., Dascal N., Gillis D.,
RA Hanukoglu A.;
RT "Truncated beta epithelial sodium channel (ENaC) subunits responsible for
RT multi-system pseudohypoaldosteronism support partial activity of ENaC.";
RL J. Steroid Biochem. Mol. Biol. 119:84-88(2010).
RN [18]
RP TISSUE SPECIFICITY.
RX PubMed=22207244; DOI=10.1007/s00418-011-0904-1;
RA Enuka Y., Hanukoglu I., Edelheit O., Vaknine H., Hanukoglu A.;
RT "Epithelial sodium channels (ENaC) are uniformly distributed on motile
RT cilia in the oviduct and the respiratory airways.";
RL Histochem. Cell Biol. 137:339-353(2012).
RN [19]
RP INTERACTION WITH PCSK9.
RX PubMed=22493497; DOI=10.1074/jbc.m112.363382;
RA Sharotri V., Collier D.M., Olson D.R., Zhou R., Snyder P.M.;
RT "Regulation of epithelial sodium channel trafficking by proprotein
RT convertase subtilisin/kexin type 9 (PCSK9).";
RL J. Biol. Chem. 287:19266-19274(2012).
RN [20]
RP INTERACTION WITH BPIFA1, AND GLYCOSYLATION.
RX PubMed=24124190; DOI=10.1152/ajplung.00103.2013;
RA Hobbs C.A., Blanchard M.G., Alijevic O., Tan C.D., Kellenberger S.,
RA Bencharit S., Cao R., Kesimer M., Walton W.G., Henderson A.G.,
RA Redinbo M.R., Stutts M.J., Tarran R.;
RT "Identification of the SPLUNC1 ENaC-inhibitory domain yields novel
RT strategies to treat sodium hyperabsorption in cystic fibrosis airway
RT epithelial cultures.";
RL Am. J. Physiol. 305:L990-L1001(2013).
RN [21]
RP REVIEW.
RX PubMed=23547933; DOI=10.2174/1874467211306010005;
RA Alvarez de la Rosa D., Navarro-Gonzalez J.F., Giraldez T.;
RT "ENaC modulators and renal disease.";
RL Curr. Mol. Pharmacol. 6:35-43(2013).
RN [22]
RP INTERACTION WITH BPIFA1.
RX PubMed=24043776; DOI=10.1073/pnas.1311999110;
RA Garland A.L., Walton W.G., Coakley R.D., Tan C.D., Gilmore R.C.,
RA Hobbs C.A., Tripathy A., Clunes L.A., Bencharit S., Stutts M.J., Betts L.,
RA Redinbo M.R., Tarran R.;
RT "Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis
RT airways.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:15973-15978(2013).
RN [23]
RP PHYLOGENETIC ANALYSIS, AND NOMENCLATURE.
RX PubMed=26772908; DOI=10.1016/j.gene.2015.12.061;
RA Hanukoglu I., Hanukoglu A.;
RT "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function,
RT tissue distribution, and associated inherited diseases.";
RL Gene 579:95-132(2016).
RN [24]
RP VARIANT LIDLS1 LEU-616.
RX PubMed=7550319; DOI=10.1038/ng0995-76;
RA Hansson J.H., Nelson-Williams C., Suzuki H., Schild L., Shimkets R.A.,
RA Lu Y., Canessa C.M., Iwasaki T., Rossier B.C., Lifton R.P.;
RT "Hypertension caused by a truncated epithelial sodium channel gamma
RT subunit: genetic heterogeneity of Liddle syndrome.";
RL Nat. Genet. 11:76-82(1995).
RN [25]
RP VARIANT LIDLS1 LEU-616.
RX PubMed=8524790; DOI=10.1073/pnas.92.25.11495;
RA Hansson J.H., Schild L., Lu Y., Wilson T.A., Gautschi I., Shimkets R.A.,
RA Nelson-Williams C., Rossier B.C., Lifton R.P.;
RT "A de novo missense mutation of the beta subunit of the epithelial sodium
RT channel causes hypertension and Liddle syndrome, identifying a proline-rich
RT segment critical for regulation of channel activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:11495-11499(1995).
RN [26]
RP VARIANT LIDLS1 HIS-620, AND CHARACTERIZATION OF VARIANT LIDLS1 HIS-620.
RX PubMed=8601645; DOI=10.1172/jci118606;
RA Tamura H., Schild L., Enomoto N., Matsui N., Marumo F., Rossier B.C.;
RT "Liddle disease caused by a missense mutation of beta subunit of the
RT epithelial sodium channel gene.";
RL J. Clin. Invest. 97:1780-1784(1996).
RN [27]
RP VARIANT PHA1B SER-37.
RX PubMed=8589714; DOI=10.1038/ng0396-248;
RA Chang S.S., Grunder S., Hanukoglu A., Roesler A., Mathew P.M.,
RA Hanukoglu I., Schild L., Lu Y., Shimkets R.A., Nelson-Williams C.,
RA Rossier B.C., Lifton R.P.;
RT "Mutations in subunits of the epithelial sodium channel cause salt wasting
RT with hyperkalaemic acidosis, pseudohypoaldosteronism type 1.";
RL Nat. Genet. 12:248-253(1996).
RN [28]
RP VARIANTS MET-434; VAL-442; SER-589; MET-594; HIS-597; CYS-624 AND GLY-632.
RX PubMed=9674649; DOI=10.1161/01.hyp.32.1.129;
RA Persu A., Barbry P., Bassilana F., Houot A.-M., Mengual R., Lazdunski M.,
RA Corvol P., Jeunemaitre X.;
RT "Genetic analysis of the beta subunit of the epithelial Na+ channel in
RT essential hypertension.";
RL Hypertension 32:129-137(1998).
RN [29]
RP VARIANT LIDLS1 SER-617.
RX PubMed=9626162; DOI=10.1210/jcem.83.6.5030;
RA Inoue J., Iwaoka T., Tokunaga H., Takamune K., Naomi S., Araki M.,
RA Takahama K., Yamaguchi K., Tomita K.;
RT "A family with Liddle's syndrome caused by a new missense mutation in the
RT beta subunit of the epithelial sodium channel.";
RL J. Clin. Endocrinol. Metab. 83:2210-2213(1998).
RN [30]
RP VARIANTS LIDLS1 LEU-616 AND SER-616.
RX PubMed=9794716; DOI=10.1097/00004872-199816080-00008;
RA Uehara Y., Sasaguri M., Kinoshita A., Tsuji E., Kiyose H., Taniguchi H.,
RA Noda K., Ideishi M., Inoue J., Tomita K., Arakawa K.;
RT "Genetic analysis of the epithelial sodium channel in Liddle's syndrome.";
RL J. Hypertens. 16:1131-1135(1998).
RN [31]
RP VARIANT PRO-336.
RX PubMed=10404817; DOI=10.1210/jcem.84.7.5857;
RA Arai K., Zachman K., Shibasaki T., Chrousos G.P.;
RT "Polymorphisms of amiloride-sensitive sodium channel subunits in five
RT sporadic cases of pseudohypoaldosteronism: do they have pathologic
RT potential?";
RL J. Clin. Endocrinol. Metab. 84:2434-2437(1999).
RN [32]
RP VARIANT GLN-563, AND ASSOCIATION WITH HYPERTENSION.
RX PubMed=12714866; DOI=10.1097/00004872-200305000-00016;
RA Rayner B.L., Owen E.P., King J.A., Soule S.G., Vreede H., Opie L.H.,
RA Marais D., Davidson J.S.;
RT "A new mutation, R563Q, of the beta subunit of the epithelial sodium
RT channel associated with low-renin, low-aldosterone hypertension.";
RL J. Hypertens. 21:921-926(2003).
RN [33]
RP INVOLVEMENT IN PSEUDOHYPOALDOSTERONISM TYPE 1.
RX PubMed=15853823; DOI=10.1111/j.1365-2265.2005.02255.x;
RA Edelheit O., Hanukoglu I., Gizewska M., Kandemir N., Tenenbaum-Rakover Y.,
RA Yurdakoek M., Zajaczek S., Hanukoglu A.;
RT "Novel mutations in epithelial sodium channel (ENaC) subunit genes and
RT phenotypic expression of multisystem pseudohypoaldosteronism.";
RL Clin. Endocrinol. (Oxf.) 62:547-553(2005).
RN [34]
RP VARIANTS BESC1 CYS-82; LEU-267; SER-294 AND LYS-539, AND CHARACTERIZATION
RP OF VARIANTS BESC1 LEU-267; SER-294 AND LYS-539.
RX PubMed=16207733; DOI=10.1093/hmg/ddi374;
RA Sheridan M.B., Fong P., Groman J.D., Conrad C., Flume P., Diaz R.,
RA Harris C., Knowles M., Cutting G.R.;
RT "Mutations in the beta-subunit of the epithelial Na+ channel in patients
RT with a cystic fibrosis-like syndrome.";
RL Hum. Mol. Genet. 14:3493-3498(2005).
RN [35]
RP VARIANT LIDLS1 ARG-618.
RX PubMed=15483078; DOI=10.1210/jc.2004-1027;
RA Furuhashi M., Kitamura K., Adachi M., Miyoshi T., Wakida N., Ura N.,
RA Shikano Y., Shinshi Y., Sakamoto K., Hayashi M., Satoh N., Nishitani T.,
RA Tomita K., Shimamoto K.;
RT "Liddle's syndrome caused by a novel mutation in the proline-rich PY motif
RT of the epithelial sodium channel beta-subunit.";
RL J. Clin. Endocrinol. Metab. 90:340-344(2005).
RN [36]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-311; VAL-314 AND VAL-387.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [37]
RP VARIANTS BESC1 CYS-82; SER-288 AND THR-369.
RX PubMed=18507830; DOI=10.1186/1465-9921-9-46;
RA Fajac I., Viel M., Sublemontier S., Hubert D., Bienvenu T.;
RT "Could a defective epithelial sodium channel lead to bronchiectasis.";
RL Respir. Res. 9:46-46(2008).
RN [38]
RP VARIANT BESC1 MET-348, AND VARIANT VAL-442.
RX PubMed=19017867; DOI=10.1378/chest.08-2246;
RA Mutesa L., Azad A.K., Verhaeghe C., Segers K., Vanbellinghen J.F.,
RA Ngendahayo L., Rusingiza E.K., Mutwa P.R., Rulisa S., Koulischer L.,
RA Cassiman J.J., Cuppens H., Bours V.;
RT "Genetic analysis of Rwandan patients with cystic fibrosis-like symptoms:
RT identification of novel cystic fibrosis transmembrane conductance regulator
RT and epithelial sodium channel gene variants.";
RL Chest 135:1233-1242(2009).
CC -!- FUNCTION: Sodium permeable non-voltage-sensitive ion channel inhibited
CC by the diuretic amiloride. Mediates the electrodiffusion of the luminal
CC sodium (and water, which follows osmotically) through the apical
CC membrane of epithelial cells. Plays an essential role in electrolyte
CC and blood pressure homeostasis, but also in airway surface liquid
CC homeostasis, which is important for proper clearance of mucus. Controls
CC the reabsorption of sodium in kidney, colon, lung and sweat glands.
CC Also plays a role in taste perception. {ECO:0000269|PubMed:7762608,
CC ECO:0000303|PubMed:7490094}.
CC -!- ACTIVITY REGULATION: Activated by WNK1, WNK2, WNK3 and WNK4.
CC {ECO:0000250|UniProtKB:Q9WU38}.
CC -!- SUBUNIT: Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a
CC gamma/SCNN1G subunit. An additional delta/SCNN1D subunit exists only in
CC some organisms and can replace the alpha/SCNN1A subunit to form an
CC alternative channel with specific properties (PubMed:7499195,
CC PubMed:16423824). Interacts with NEDD4 (via WW domains)
CC (PubMed:11244092, PubMed:12167593). Interacts with NEDD4L (via WW
CC domains) (PubMed:11244092). Interacts with WWP1 (via WW domains)
CC (PubMed:9169421). Interacts with WWP2 (via WW domains) (PubMed:9169421,
CC PubMed:12167593). Interacts with the full-length immature form of PCSK9
CC (pro-PCSK9) (PubMed:22493497). Interacts (N-glycosylated) with BPIFA1;
CC the interaction is direct and inhibits the proteolytic processing of
CC SCNN1A and SCNN1G and the activation of ENaC (PubMed:24124190,
CC PubMed:24043776). {ECO:0000269|PubMed:11244092,
CC ECO:0000269|PubMed:12167593, ECO:0000269|PubMed:16423824,
CC ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:24043776,
CC ECO:0000269|PubMed:24124190, ECO:0000269|PubMed:7499195,
CC ECO:0000269|PubMed:9169421}.
CC -!- INTERACTION:
CC P51168; P46934: NEDD4; NbExp=5; IntAct=EBI-2547187, EBI-726944;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000305|PubMed:7490094}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P37089}. Cytoplasmic vesicle membrane
CC {ECO:0000250|UniProtKB:P37090}. Note=Apical membrane of epithelial
CC cells. {ECO:0000305|PubMed:7490094}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P51168-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P51168-2; Sequence=VSP_007724;
CC -!- TISSUE SPECIFICITY: Detected in placenta, lung and kidney
CC (PubMed:7762608). Expressed in kidney (at protein level)
CC (PubMed:22207244). {ECO:0000269|PubMed:22207244,
CC ECO:0000269|PubMed:7762608}.
CC -!- PTM: Phosphorylated on serine and threonine residues. Aldosterone and
CC insulin increase the basal level of phosphorylation.
CC {ECO:0000250|UniProtKB:P37090}.
CC -!- PTM: N-glycosylated. N-glycosylation is required for interaction with
CC BPIFA1. {ECO:0000269|PubMed:24124190, ECO:0000269|PubMed:7762608}.
CC -!- DISEASE: Pseudohypoaldosteronism 1, autosomal recessive (PHA1B)
CC [MIM:264350]: A rare salt wasting disease resulting from target organ
CC unresponsiveness to mineralocorticoids. PHA1B is a severe form
CC involving multiple organ systems, and characterized by an often
CC fulminant presentation in the neonatal period with dehydration,
CC hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive and
CC weight loss. {ECO:0000269|PubMed:8589714}. Note=The disease is caused
CC by variants affecting the gene represented in this entry. The degree of
CC channel function impairment differentially affects the renin-
CC aldosterone system and urinary Na/K ratios, resulting in distinct
CC genotype-phenotype relationships in PHA1 patients. Loss-of-function
CC mutations are associated with a severe clinical course and age-
CC dependent hyperactivation of the renin-aldosterone system. This feature
CC is not observed in patients with missense mutations that reduce but do
CC not eliminate channel function. Markedly reduced channel activity
CC results in impaired linear growth and delayed puberty
CC (PubMed:18634878). {ECO:0000269|PubMed:18634878}.
CC -!- DISEASE: Liddle syndrome 1 (LIDLS1) [MIM:177200]: A form of Liddle
CC syndrome, an autosomal dominant disorder characterized by early onset
CC of hypertension, hypokalemic alkalosis, and suppression of plasma renin
CC activity and aldosterone secretion. {ECO:0000269|PubMed:15483078,
CC ECO:0000269|PubMed:7550319, ECO:0000269|PubMed:8524790,
CC ECO:0000269|PubMed:8601645, ECO:0000269|PubMed:9626162,
CC ECO:0000269|PubMed:9794716}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Bronchiectasis with or without elevated sweat chloride 1
CC (BESC1) [MIM:211400]: A debilitating respiratory disease characterized
CC by chronic, abnormal dilatation of the bronchi and other cystic
CC fibrosis-like symptoms in the absence of known causes of bronchiectasis
CC (cystic fibrosis, autoimmune diseases, ciliary dyskinesia, common
CC variable immunodeficiency, foreign body obstruction). Clinical features
CC include sub-normal lung function, sinopulmonary infections, chronic
CC productive cough, excessive sputum production, and elevated sweat
CC chloride in some cases. {ECO:0000269|PubMed:16207733,
CC ECO:0000269|PubMed:18507830, ECO:0000269|PubMed:19017867}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the amiloride-sensitive sodium channel (TC
CC 1.A.6) family. SCNN1B subfamily. {ECO:0000305}.
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DR EMBL; X87159; CAA60632.1; -; mRNA.
DR EMBL; L36593; AAA75459.1; -; mRNA.
DR EMBL; AJ005383; CAA06508.2; -; Genomic_DNA.
DR EMBL; AJ005384; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005385; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005386; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005387; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005388; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005389; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005390; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005391; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005392; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; AJ005393; CAA06508.2; JOINED; Genomic_DNA.
DR EMBL; FJ515831; ACS13723.1; -; Genomic_DNA.
DR EMBL; BC036352; AAH36352.2; -; mRNA.
DR EMBL; AC130452; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF260226; AAK49394.1; -; mRNA.
DR EMBL; U16023; AAA67036.1; -; Genomic_DNA.
DR CCDS; CCDS10609.1; -. [P51168-1]
DR PIR; I51915; I51915.
DR RefSeq; NP_000327.2; NM_000336.2. [P51168-1]
DR PDB; 6BQN; EM; 3.90 A; B=73-515.
DR PDB; 6WTH; EM; 3.06 A; B=1-640.
DR PDBsum; 6BQN; -.
DR PDBsum; 6WTH; -.
DR AlphaFoldDB; P51168; -.
DR SMR; P51168; -.
DR BioGRID; 112242; 20.
DR ComplexPortal; CPX-2188; Amiloride-sensitive sodium channel complex, alpha-beta-gamma.
DR ComplexPortal; CPX-312; Amiloride-sensitive sodium channel complex, delta-alpha-beta-gamma.
DR ComplexPortal; CPX-313; Amiloride-sensitive sodium channel complex, delta-beta-gamma.
DR CORUM; P51168; -.
DR ELM; P51168; -.
DR IntAct; P51168; 4.
DR MINT; P51168; -.
DR STRING; 9606.ENSP00000345751; -.
DR ChEMBL; CHEMBL1628483; -.
DR DrugBank; DB00594; Amiloride.
DR DrugBank; DB14509; Lithium carbonate.
DR DrugBank; DB00384; Triamterene.
DR DrugCentral; P51168; -.
DR GuidetoPHARMACOLOGY; 739; -.
DR TCDB; 1.A.6.1.1; the epithelial na(+) channel (enac) family.
DR GlyGen; P51168; 4 sites.
DR iPTMnet; P51168; -.
DR PhosphoSitePlus; P51168; -.
DR BioMuta; SCNN1B; -.
DR DMDM; 8928561; -.
DR EPD; P51168; -.
DR MassIVE; P51168; -.
DR PaxDb; P51168; -.
DR PeptideAtlas; P51168; -.
DR PRIDE; P51168; -.
DR ProteomicsDB; 56295; -. [P51168-1]
DR ProteomicsDB; 56296; -. [P51168-2]
DR Antibodypedia; 2607; 480 antibodies from 31 providers.
DR DNASU; 6338; -.
DR Ensembl; ENST00000307331.9; ENSP00000302874.5; ENSG00000168447.11. [P51168-2]
DR Ensembl; ENST00000343070.7; ENSP00000345751.2; ENSG00000168447.11. [P51168-1]
DR GeneID; 6338; -.
DR KEGG; hsa:6338; -.
DR MANE-Select; ENST00000343070.7; ENSP00000345751.2; NM_000336.3; NP_000327.2.
DR UCSC; uc002dln.3; human. [P51168-1]
DR CTD; 6338; -.
DR DisGeNET; 6338; -.
DR GeneCards; SCNN1B; -.
DR HGNC; HGNC:10600; SCNN1B.
DR HPA; ENSG00000168447; Tissue enhanced (esophagus, intestine, vagina).
DR MalaCards; SCNN1B; -.
DR MIM; 177200; phenotype.
DR MIM; 211400; phenotype.
DR MIM; 264350; phenotype.
DR MIM; 600760; gene.
DR neXtProt; NX_P51168; -.
DR OpenTargets; ENSG00000168447; -.
DR Orphanet; 171876; Generalized pseudohypoaldosteronism type 1.
DR Orphanet; 60033; Idiopathic bronchiectasis.
DR Orphanet; 526; Liddle syndrome.
DR PharmGKB; PA306; -.
DR VEuPathDB; HostDB:ENSG00000168447; -.
DR eggNOG; KOG4294; Eukaryota.
DR GeneTree; ENSGT00940000160893; -.
DR InParanoid; P51168; -.
DR OrthoDB; 686369at2759; -.
DR PhylomeDB; P51168; -.
DR TreeFam; TF330663; -.
DR PathwayCommons; P51168; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR Reactome; R-HSA-9730628; Sensory perception of salty taste.
DR SignaLink; P51168; -.
DR SIGNOR; P51168; -.
DR BioGRID-ORCS; 6338; 7 hits in 1067 CRISPR screens.
DR ChiTaRS; SCNN1B; human.
DR GeneWiki; SCNN1B; -.
DR GenomeRNAi; 6338; -.
DR Pharos; P51168; Tclin.
DR PRO; PR:P51168; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; P51168; protein.
DR Bgee; ENSG00000168447; Expressed in lower esophagus mucosa and 125 other tissues.
DR ExpressionAtlas; P51168; baseline and differential.
DR Genevisible; P51168; HS.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0034706; C:sodium channel complex; IDA:UniProtKB.
DR GO; GO:0015280; F:ligand-gated sodium channel activity; IEA:Ensembl.
DR GO; GO:0050699; F:WW domain binding; IPI:BHF-UCL.
DR GO; GO:0032341; P:aldosterone metabolic process; IEA:Ensembl.
DR GO; GO:0014824; P:artery smooth muscle contraction; IEA:Ensembl.
DR GO; GO:0071468; P:cellular response to acidic pH; IDA:ComplexPortal.
DR GO; GO:1904045; P:cellular response to aldosterone; IC:ComplexPortal.
DR GO; GO:0036254; P:cellular response to amiloride; IDA:ComplexPortal.
DR GO; GO:1904117; P:cellular response to vasopressin; IC:ComplexPortal.
DR GO; GO:0006883; P:cellular sodium ion homeostasis; IDA:ComplexPortal.
DR GO; GO:0042045; P:epithelial fluid transport; IEA:Ensembl.
DR GO; GO:0034101; P:erythrocyte homeostasis; IEA:Ensembl.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0002269; P:leukocyte activation involved in inflammatory response; IEA:Ensembl.
DR GO; GO:0070254; P:mucus secretion; IEA:Ensembl.
DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl.
DR GO; GO:0050891; P:multicellular organismal water homeostasis; IDA:UniProtKB.
DR GO; GO:0002283; P:neutrophil activation involved in immune response; IEA:Ensembl.
DR GO; GO:0070944; P:neutrophil-mediated killing of bacterium; IEA:Ensembl.
DR GO; GO:0055075; P:potassium ion homeostasis; IEA:Ensembl.
DR GO; GO:0008217; P:regulation of blood pressure; IC:ComplexPortal.
DR GO; GO:0032094; P:response to food; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0050914; P:sensory perception of salty taste; IC:ComplexPortal.
DR GO; GO:0050915; P:sensory perception of sour taste; IC:ComplexPortal.
DR GO; GO:0055078; P:sodium ion homeostasis; IDA:UniProtKB.
DR GO; GO:0098719; P:sodium ion import across plasma membrane; IDA:ComplexPortal.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006814; P:sodium ion transport; TAS:ProtInc.
DR GO; GO:0097274; P:urea homeostasis; IEA:Ensembl.
DR InterPro; IPR001873; ENaC.
DR InterPro; IPR004724; ENaC_chordates.
DR InterPro; IPR020903; ENaC_CS.
DR PANTHER; PTHR11690; PTHR11690; 1.
DR Pfam; PF00858; ASC; 1.
DR PRINTS; PR01078; AMINACHANNEL.
DR TIGRFAMs; TIGR00859; ENaC; 1.
DR PROSITE; PS01206; ASC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cytoplasmic vesicle;
KW Disease variant; Glycoprotein; Ion channel; Ion transport; Membrane;
KW Phosphoprotein; Reference proteome; Sensory transduction; Sodium;
KW Sodium channel; Sodium transport; Taste; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..640
FT /note="Amiloride-sensitive sodium channel subunit beta"
FT /id="PRO_0000181268"
FT TOPO_DOM 1..50
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P37089"
FT TRANSMEM 51..71
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 72..532
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P37089"
FT TRANSMEM 533..553
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 554..640
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P37089"
FT REGION 590..640
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 591..605
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 633
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9WU38"
FT MOD_RES 635
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9WU38"
FT CARBOHYD 260
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1
FT /note="M -> MLLHINPAYLFKLLHGFPPWIMPTDGNLGDKNFQMGKPGHREGATM
FT (in isoform 2)"
FT /evidence="ECO:0000303|Ref.8"
FT /id="VSP_007724"
FT VARIANT 37
FT /note="G -> S (in PHA1B; dbSNP:rs137852706)"
FT /evidence="ECO:0000269|PubMed:8589714"
FT /id="VAR_007127"
FT VARIANT 82
FT /note="S -> C (in BESC1; dbSNP:rs35731153)"
FT /evidence="ECO:0000269|PubMed:16207733,
FT ECO:0000269|PubMed:18507830"
FT /id="VAR_062401"
FT VARIANT 267
FT /note="P -> L (in BESC1; decreased channel activity;
FT dbSNP:rs137852709)"
FT /evidence="ECO:0000269|PubMed:16207733"
FT /id="VAR_062402"
FT VARIANT 288
FT /note="N -> S (in BESC1; dbSNP:rs137852712)"
FT /evidence="ECO:0000269|PubMed:18507830"
FT /id="VAR_062403"
FT VARIANT 294
FT /note="G -> S (in BESC1; increased channel activity;
FT dbSNP:rs72654338)"
FT /evidence="ECO:0000269|PubMed:16207733"
FT /id="VAR_062404"
FT VARIANT 311
FT /note="A -> V (in a colorectal cancer sample; somatic
FT mutation; dbSNP:rs777888930)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036480"
FT VARIANT 314
FT /note="A -> V (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036481"
FT VARIANT 336
FT /note="A -> P"
FT /evidence="ECO:0000269|PubMed:10404817,
FT ECO:0000269|PubMed:7762608"
FT /id="VAR_015836"
FT VARIANT 348
FT /note="V -> M (in BESC1; dbSNP:rs61759921)"
FT /evidence="ECO:0000269|PubMed:19017867"
FT /id="VAR_062405"
FT VARIANT 369
FT /note="P -> T (in BESC1; dbSNP:rs137852711)"
FT /evidence="ECO:0000269|PubMed:18507830"
FT /id="VAR_062406"
FT VARIANT 387
FT /note="L -> V (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036482"
FT VARIANT 434
FT /note="V -> M (in dbSNP:rs201330438)"
FT /evidence="ECO:0000269|PubMed:9674649"
FT /id="VAR_015837"
FT VARIANT 442
FT /note="G -> V (in dbSNP:rs1799980)"
FT /evidence="ECO:0000269|PubMed:19017867,
FT ECO:0000269|PubMed:9674649"
FT /id="VAR_014891"
FT VARIANT 539
FT /note="E -> K (in BESC1; decreased channel activity;
FT dbSNP:rs137852710)"
FT /evidence="ECO:0000269|PubMed:16207733"
FT /id="VAR_062407"
FT VARIANT 563
FT /note="R -> Q (associated with hypertension in South
FT African Black; dbSNP:rs149868979)"
FT /evidence="ECO:0000269|PubMed:12714866"
FT /id="VAR_026519"
FT VARIANT 589
FT /note="G -> S (in dbSNP:rs61759926)"
FT /evidence="ECO:0000269|PubMed:9674649"
FT /id="VAR_015838"
FT VARIANT 594
FT /note="T -> M (in dbSNP:rs1799979)"
FT /evidence="ECO:0000269|PubMed:9674649"
FT /id="VAR_014892"
FT VARIANT 597
FT /note="R -> H (in dbSNP:rs140945152)"
FT /evidence="ECO:0000269|PubMed:9674649"
FT /id="VAR_015839"
FT VARIANT 616
FT /note="P -> L (in LIDLS1; dbSNP:rs387906402)"
FT /evidence="ECO:0000269|PubMed:7550319,
FT ECO:0000269|PubMed:8524790, ECO:0000269|PubMed:9794716"
FT /id="VAR_007128"
FT VARIANT 616
FT /note="P -> S (in LIDLS1)"
FT /evidence="ECO:0000269|PubMed:9794716"
FT /id="VAR_007129"
FT VARIANT 617
FT /note="P -> S (in LIDLS1; dbSNP:rs137852708)"
FT /evidence="ECO:0000269|PubMed:9626162"
FT /id="VAR_026520"
FT VARIANT 618
FT /note="P -> R (in LIDLS1; dbSNP:rs137852705)"
FT /evidence="ECO:0000269|PubMed:15483078"
FT /id="VAR_026521"
FT VARIANT 620
FT /note="Y -> H (in LIDLS1; constitutive channel activation;
FT dbSNP:rs137852707)"
FT /evidence="ECO:0000269|PubMed:8601645"
FT /id="VAR_026522"
FT VARIANT 624
FT /note="R -> C (in dbSNP:rs372132399)"
FT /evidence="ECO:0000269|PubMed:9674649"
FT /id="VAR_015840"
FT VARIANT 632
FT /note="E -> G"
FT /evidence="ECO:0000269|PubMed:9674649"
FT /id="VAR_015841"
FT CONFLICT 41
FT /note="I -> T (in Ref. 6; AAH36352)"
FT /evidence="ECO:0000305"
FT CONFLICT 314
FT /note="A -> G (in Ref. 1; CAA60632)"
FT /evidence="ECO:0000305"
FT CONFLICT 498
FT /note="Y -> F (in Ref. 2; AAA75459)"
FT /evidence="ECO:0000305"
FT STRAND 79..86
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 94..103
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 105..107
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 108..111
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 113..126
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 142..145
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 150..154
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 162..165
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 186..196
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 201..210
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 211..227
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 232..236
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 242..245
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 246..251
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 258..260
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 261..266
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 267..269
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 270..276
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 279..281
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 291..293
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 294..300
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 303..305
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 308..310
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 315..321
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 323..325
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 329..331
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 340..352
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 356..358
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 359..365
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 375..377
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 383..398
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 399..402
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 417..419
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 423..431
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 434..443
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 446..453
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 456..458
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 465..467
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 468..480
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 489..491
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 492..511
FT /evidence="ECO:0007829|PDB:6WTH"
SQ SEQUENCE 640 AA; 72659 MW; 5249867F0A960E0C CRC64;
MHVKKYLLKG LHRLQKGPGY TYKELLVWYC DNTNTHGPKR IICEGPKKKA MWFLLTLLFA
ALVCWQWGIF IRTYLSWEVS VSLSVGFKTM DFPAVTICNA SPFKYSKIKH LLKDLDELME
AVLERILAPE LSHANATRNL NFSIWNHTPL VLIDERNPHH PMVLDLFGDN HNGLTSSSAS
EKICNAHGCK MAMRLCSLNR TQCTFRNFTS ATQALTEWYI LQATNIFAQV PQQELVEMSY
PGEQMILACL FGAEPCNYRN FTSIFYPHYG NCYIFNWGMT EKALPSANPG TEFGLKLILD
IGQEDYVPFL ASTAGVRLML HEQRSYPFIR DEGIYAMSGT ETSIGVLVDK LQRMGEPYSP
CTVNGSEVPV QNFYSDYNTT YSIQACLRSC FQDHMIRNCN CGHYLYPLPR GEKYCNNRDF
PDWAHCYSDL QMSVAQRETC IGMCKESCND TQYKMTISMA DWPSEASEDW IFHVLSQERD
QSTNITLSRK GIVKLNIYFQ EFNYRTIEES AANNIVWLLS NLGGQFGFWM GGSVLCLIEF
GEIIIDFVWI TIIKLVALAK SLRQRRAQAS YAGPPPTVAE LVEAHTNFGF QPDTAPRSPN
TGPYPSEQAL PIPGTPPPNY DSLRLQPLDV IESDSEGDAI
