SCNNA_HUMAN
ID SCNNA_HUMAN Reviewed; 669 AA.
AC P37088; A5X2U9; B4E2Q5; C5HTZ0; O43271; Q6GSQ6; Q9UM64;
DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1994, sequence version 1.
DT 03-AUG-2022, entry version 217.
DE RecName: Full=Amiloride-sensitive sodium channel subunit alpha;
DE AltName: Full=Alpha-NaCH;
DE AltName: Full=Epithelial Na(+) channel subunit alpha;
DE Short=Alpha-ENaC;
DE Short=ENaCA;
DE AltName: Full=Nonvoltage-gated sodium channel 1 subunit alpha;
DE AltName: Full=SCNEA;
GN Name=SCNN1A; Synonyms=SCNN1;
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), AND FUNCTION.
RC TISSUE=Lung;
RX PubMed=8278374; DOI=10.1073/pnas.91.1.247;
RA Voilley N., Lingueglia E., Champigny G., Mattei M.-G., Waldmann R.,
RA Lazdunski M., Barbry P.;
RT "The lung amiloride-sensitive Na+ channel: biophysical properties,
RT pharmacology, ontogenesis, and molecular cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:247-251(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Kidney;
RX PubMed=8023962; DOI=10.1152/ajplung.1994.266.6.l728;
RA McDonald F.J., Snyder P.M., McCray P.B. Jr., Welsh M.J.;
RT "Cloning, expression, and tissue distribution of a human amiloride-
RT sensitive Na+ channel.";
RL Am. J. Physiol. 266:L728-L734(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9654208; DOI=10.1007/s004390050743;
RA Ludwig M., Bolkenius U., Wickert L., Marynen P., Bidlingmaier F.;
RT "Structural organisation of the gene encoding the alpha-subunit of the
RT human amiloride-sensitive epithelial sodium channel.";
RL Hum. Genet. 102:576-581(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10447117; DOI=10.1203/00006450-199908000-00014;
RA Chow Y.H., Wang Y., Plumb J., O'Brodovich H., Hu J.;
RT "Hormonal regulation and genomic organization of the human amiloride-
RT sensitive epithelial sodium channel alpha subunit gene.";
RL Pediatr. Res. 46:208-214(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-663.
RC TISSUE=Nasal epithelium;
RX PubMed=17766193; DOI=10.1016/j.jcf.2007.07.012;
RA Bangel N., Dahlhoff C., Sobczak K., Weber W.M., Kusche-Vihrog K.;
RT "Upregulated expression of ENaC in human CF nasal epithelium.";
RL J. Cyst. Fibros. 7:197-205(2008).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6).
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ALA-663.
RC TISSUE=Colon, and Lung;
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 [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50, AND ALTERNATIVE SPLICING
RP (ISOFORMS 1 AND 2).
RC TISSUE=Kidney;
RX PubMed=9612219; DOI=10.1152/ajpcell.1998.274.5.c1312;
RA Thomas C.P., Auerbach S.D., Stokes J.B., Volk K.A.;
RT "5' heterogeneity in epithelial sodium channel alpha-subunit mRNA leads to
RT distinct NH2-terminal variant proteins.";
RL Am. J. Physiol. 274:C1312-C1323(1998).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50 (ISOFORMS 1 AND 2), AND
RP INDUCTION.
RC TISSUE=Placenta;
RX PubMed=11266509; DOI=10.1210/mend.15.4.0620;
RA Mick V.E., Itani O.A., Loftus R.W., Husted R.F., Schmidt T.J., Thomas C.P.;
RT "The alpha-subunit of the epithelial sodium channel is an aldosterone-
RT induced transcript in mammalian collecting ducts, and this transcriptional
RT response is mediated via distinct cis-elements in the 5'-flanking region of
RT the gene.";
RL Mol. Endocrinol. 15:575-588(2001).
RN [13]
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 [14]
RP ALTERNATIVE SPLICING (ISOFORMS 1; 3; 4 AND 5), AND TISSUE SPECIFICITY.
RX PubMed=9575806; DOI=10.1152/ajpcell.1998.274.4.c1081;
RA Tucker J.K., Tamba K., Lee Y.-J., Shen L.-L., Warnock D.G., Oh Y.;
RT "Cloning and functional studies of splice variants of the alpha-subunit of
RT the amiloride-sensitive Na+ channel.";
RL Am. J. Physiol. 274:C1081-C1089(1998).
RN [15]
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 [16]
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 [17]
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 [18]
RP PROTEOLYTIC PROCESSING.
RX PubMed=18650438; DOI=10.1074/jbc.m803931200;
RA Carattino M.D., Hughey R.P., Kleyman T.R.;
RT "Proteolytic processing of the epithelial sodium channel gamma subunit has
RT a dominant role in channel activation.";
RL J. Biol. Chem. 283:25290-25295(2008).
RN [19]
RP GENOTYPE-PHENOTYPE RELATIONSHIPS IN PHA1B, LONG-TERM EFFECTS OF MUTATIONS
RP ON PHA1B, VARIANT PHA1B CYS-327, AND CHARACTERIZATION OF VARIANT PHA1B
RP CYS-327.
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 [20]
RP SUBCELLULAR LOCATION, AND 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 [21]
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 [22]
RP FUNCTION, AND SUBCELLULAR LOCATION.
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 [23]
RP INTERACTION WITH NEDD4.
RX PubMed=23665454; DOI=10.1016/j.bbapap.2013.04.031;
RA Bobby R., Medini K., Neudecker P., Lee T.V., Brimble M.A., McDonald F.J.,
RA Lott J.S., Dingley A.J.;
RT "Structure and dynamics of human Nedd4-1 WW3 in complex with the alphaENaC
RT PY motif.";
RL Biochim. Biophys. Acta 1834:1632-1641(2013).
RN [24]
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 [25]
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 [26]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=28130590; DOI=10.1007/s00418-016-1535-3;
RA Hanukoglu I., Boggula V.R., Vaknine H., Sharma S., Kleyman T.,
RA Hanukoglu A.;
RT "Expression of epithelial sodium channel (ENaC) and CFTR in the human
RT epidermis and epidermal appendages.";
RL Histochem. Cell Biol. 147:733-748(2017).
RN [27]
RP VARIANTS THR-334; PHE-618 AND ALA-663.
RX PubMed=10523338; DOI=10.1161/01.hyp.34.4.631;
RA Ambrosius W.T., Bloem L.J., Zhou L., Rebhun J.F., Snyder P.M., Wagner M.A.,
RA Guo C., Pratt J.H.;
RT "Genetic variants in the epithelial sodium channel in relation to
RT aldosterone and potassium excretion and risk for hypertension.";
RL Hypertension 34:631-637(1999).
RN [28]
RP ERRATUM OF PUBMED:10523338.
RA Ambrosius W.T., Bloem L.J., Zhou L., Rebhun J.F., Snyder P.M., Wagner M.A.,
RA Guo C., Pratt J.H.;
RL Hypertension 41:1E-1E(2003).
RN [29]
RP INTERACTION WITH NEDD4 AND NEDD4L.
RX PubMed=11696533; DOI=10.1074/jbc.c100623200;
RA Snyder P.M., Olson D.R., Thomas B.C.;
RT "Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated
RT inhibition of the epithelial Na+ channel.";
RL J. Biol. Chem. 277:5-8(2002).
RN [30]
RP INVOLVEMENT IN LIDLS3, VARIANT LIDLS3 ARG-479, FUNCTION, CHARACTERIZATION
RP OF VARIANT LIDLS3 ARG-479, AND MUTAGENESIS OF CYS-394.
RX PubMed=28710092; DOI=10.1681/asn.2016111163;
RA Salih M., Gautschi I., van Bemmelen M.X., Di Benedetto M., Brooks A.S.,
RA Lugtenberg D., Schild L., Hoorn E.J.;
RT "A Missense Mutation in the Extracellular Domain of alphaENaC Causes Liddle
RT Syndrome.";
RL J. Am. Soc. Nephrol. 28:3291-3299(2017).
RN [31]
RP VARIANT ALA-663.
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 PHA1B LEU-562, AND VARIANT ARG-493.
RX PubMed=10586178; DOI=10.1016/s0022-3476(99)70094-6;
RA Schaedel C., Marthinsen L., Kristoffersson A.-C., Kornfalt R.,
RA Nilsson K.O., Orlenius B., Holmberg L.;
RT "Lung symptoms in pseudohypoaldosteronism type 1 are associated with
RT deficiency of the alpha-subunit of the epithelial sodium channel.";
RL J. Pediatr. 135:739-745(1999).
RN [33]
RP VARIANT ALA-663.
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 [34]
RP VARIANT ALA-663, AND ASSOCIATION OF VARIANT ARG-493 WITH RISK FOR ISCHEMIC
RP CEREBROVASCULAR EVENTS.
RX PubMed=15734793; DOI=10.1373/clinchem.2004.046276;
RA Hsieh K., Lalouschek W., Schillinger M., Endler G., Reisinger M.,
RA Janisiw M., Lang W., Cheng S., Wagner O., Mannhalter C.;
RT "Impact of alphaENaC polymorphisms on the risk of ischemic cerebrovascular
RT events: a multicenter case-control study.";
RL Clin. Chem. 51:952-956(2005).
RN [35]
RP VARIANT PHA1B CYS-327.
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 [36]
RP VARIANT TRP-181.
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 [37]
RP VARIANTS BESC2 LEU-61 AND ILE-114, VARIANTS TRP-181; THR-334; ARG-493 AND
RP ALA-663, CHARACTERIZATION OF VARIANTS BESC2 LEU-61 AND ILE-114, AND
RP CHARACTERIZATION OF VARIANTS TRP-181; THR-334 AND ARG-493.
RX PubMed=19462466; DOI=10.1002/humu.21011;
RA Azad A.K., Rauh R., Vermeulen F., Jaspers M., Korbmacher J., Boissier B.,
RA Bassinet L., Fichou Y., des Georges M., Stanke F., De Boeck K., Dupont L.,
RA Balascakova M., Hjelte L., Lebecque P., Radojkovic D., Castellani C.,
RA Schwartz M., Stuhrmann M., Schwarz M., Skalicka V., de Monestrol I.,
RA Girodon E., Ferec C., Claustres M., Tuemmler B., Cassiman J.-J.,
RA Korbmacher C., Cuppens H.;
RT "Mutations in the amiloride-sensitive epithelial sodium channel in patients
RT with cystic fibrosis-like disease.";
RL Hum. Mutat. 30:1093-1103(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 eccrine sweat
CC glands. Also plays a role in taste perception.
CC {ECO:0000269|PubMed:24124190, ECO:0000269|PubMed:28710092,
CC ECO:0000269|PubMed:8278374}.
CC -!- ACTIVITY REGULATION: Activated by WNK1, WNK2, WNK3 and WNK4.
CC {ECO:0000250|UniProtKB:Q61180}.
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 (By similarity). Interacts
CC with NEDD4 (via WW domains) (PubMed:11244092, PubMed:11696533,
CC PubMed:12167593, PubMed:23665454). Interacts with NEDD4L (via WW
CC domains) (PubMed:11244092, PubMed:11696533). Interacts with WWP1 (via
CC WW domains) (PubMed:9169421). Interacts with WWP2 (via WW domains)
CC (PubMed:12167593, PubMed:9169421). Interacts with the full-length
CC immature form of PCSK9 (pro-PCSK9) (PubMed:22493497).
CC {ECO:0000250|UniProtKB:Q61180, ECO:0000269|PubMed:11244092,
CC ECO:0000269|PubMed:11696533, ECO:0000269|PubMed:12167593,
CC ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:23665454,
CC ECO:0000269|PubMed:9169421}.
CC -!- INTERACTION:
CC P37088; P46934: NEDD4; NbExp=3; IntAct=EBI-7845444, EBI-726944;
CC P37088; P51170: SCNN1G; NbExp=3; IntAct=EBI-7845444, EBI-2547354;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000269|PubMed:22207244, ECO:0000269|PubMed:28130590}; Multi-pass
CC membrane protein {ECO:0000250|UniProtKB:P37089}. Cell projection,
CC cilium {ECO:0000269|PubMed:22207244}. Cytoplasmic granule
CC {ECO:0000269|PubMed:28130590}. Cytoplasm {ECO:0000269|PubMed:28130590}.
CC Cytoplasmic vesicle, secretory vesicle, acrosome
CC {ECO:0000250|UniProtKB:P37089}. Cell projection, cilium, flagellum
CC {ECO:0000250|UniProtKB:P37089}. Note=In the oviduct and bronchus,
CC located on cilia in multi-ciliated cells. In endometrial non-ciliated
CC epithelial cells, restricted to apical surfaces. In epidermis, located
CC nearly uniformly in the cytoplasm in a granular distribution
CC (PubMed:28130590). In sebaceous glands, observed only in the
CC cytoplasmic space in between the lipid vesicles (PubMed:28130590). In
CC eccrine sweat glands, mainly located at the apical surface of the cells
CC facing the lumen (PubMed:28130590). In skin, in arrector pili muscle
CC cells and in adipocytes, located in the cytoplasm and colocalized with
CC actin fibers (PubMed:28130590). In spermatogonia, spermatocytes and
CC round spermatids, located in the cytoplasm (By similarity). Prior to
CC spermiation, location shifts from the cytoplasm to the spermatid tail
CC (By similarity). In spermatozoa, localizes at the acrosome and the
CC central region of the sperm flagellum (By similarity).
CC {ECO:0000250|UniProtKB:P37089, ECO:0000269|PubMed:22207244,
CC ECO:0000269|PubMed:24124190, ECO:0000269|PubMed:28130590}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=Alpha ENAC1;
CC IsoId=P37088-1; Sequence=Displayed;
CC Name=2; Synonyms=Alpha ENAC2;
CC IsoId=P37088-2; Sequence=VSP_007719;
CC Name=3; Synonyms=Alpha ENACx;
CC IsoId=P37088-3; Sequence=VSP_007720, VSP_007721;
CC Name=4; Synonyms=Alpha ENAC-19;
CC IsoId=P37088-4; Sequence=VSP_007722;
CC Name=5; Synonyms=Alpha ENAC+22;
CC IsoId=P37088-5; Sequence=VSP_007723;
CC Name=6;
CC IsoId=P37088-6; Sequence=VSP_043667;
CC -!- TISSUE SPECIFICITY: Expressed in the female reproductive tract, from
CC the fimbrial end of the fallopian tube to the endometrium (at protein
CC level) (PubMed:22207244). Expressed in kidney (at protein level). In
CC the respiratory tract, expressed in the bronchial epithelium (at
CC protein level). Highly expressed in lung. Detected at intermediate
CC levels in pancreas and liver, and at low levels in heart and placenta
CC (PubMed:22207244). in skin, expressed in keratinocytes, melanocytes and
CC Merkel cells of the epidermal sub-layers, stratum basale, stratum
CC spinosum and stratum granulosum (at protein level) (PubMed:28130590).
CC Expressed in the outer root sheath of the hair follicles (at protein
CC level) (PubMed:28130590). Detected in both peripheral and central cells
CC of the sebaceous gland (at protein level) (PubMed:28130590). Expressed
CC by eccrine sweat glands (at protein level) (PubMed:28130590). In skin,
CC also expressed by arrector pili muscle cells and intradermal adipocytes
CC (PubMed:28130590). Isoform 1 and isoform 2 predominate in all tissues.
CC Expression of isoform 3, isoform 4 and isoform 5 is very low or not
CC detectable, except in lung and heart (PubMed:9575806).
CC {ECO:0000269|PubMed:22207244, ECO:0000269|PubMed:28130590,
CC ECO:0000269|PubMed:9575806}.
CC -!- INDUCTION: By aldosterone. {ECO:0000269|PubMed:11266509}.
CC -!- PTM: Ubiquitinated; this targets individual subunits for endocytosis
CC and proteasome-mediated degradation. {ECO:0000250|UniProtKB:P37089}.
CC -!- PTM: ENaC cleavage by furin, and subsequently by prostasin (PRSS8),
CC leads to a stepwise increase in the open probability of the channel as
CC a result of release of the alpha and gamma subunit inhibitory tracts,
CC respectively. Interaction of ENaC subunit SCNN1B with BPIFA1 protects
CC ENaC against proteolytic activation. {ECO:0000269|PubMed:18650438}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:P37089}.
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:10586178, ECO:0000269|PubMed:15853823,
CC ECO:0000269|PubMed:18634878}. Note=The disease is caused by variants
CC affecting the gene represented in this entry. The degree of channel
CC function impairment differentially affects the renin-aldosterone system
CC and urinary Na/K ratios, resulting in distinct genotype-phenotype
CC relationships in PHA1 patients. Loss-of-function mutations are
CC associated with a severe clinical course and age-dependent
CC hyperactivation of the renin-aldosterone system. This feature is not
CC observed in patients with missense mutations that reduce but do not
CC eliminate channel function. Markedly reduced channel activity results
CC in impaired linear growth and delayed puberty (PubMed:18634878).
CC {ECO:0000269|PubMed:18634878}.
CC -!- DISEASE: Bronchiectasis with or without elevated sweat chloride 2
CC (BESC2) [MIM:613021]: 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:19462466}. Note=The disease
CC is caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Liddle syndrome 3 (LIDLS3) [MIM:618126]: 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:28710092}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- MISCELLANEOUS: [Isoform 3]: Does not give rise to amiloride-sensitive
CC ion current. May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 4]: Amiloride-sensitive ion current is nearly
CC abolished. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 5]: Does not give rise to amiloride-sensitive
CC ion current. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the amiloride-sensitive sodium channel (TC
CC 1.A.6) family. SCNN1A subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH06526.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
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DR EMBL; X76180; CAA53773.1; -; mRNA.
DR EMBL; L29007; AAA21813.1; -; Genomic_DNA.
DR EMBL; Z92978; CAB07505.1; -; Genomic_DNA.
DR EMBL; Z92979; CAB07505.1; JOINED; Genomic_DNA.
DR EMBL; Z92980; CAB07505.1; JOINED; Genomic_DNA.
DR EMBL; Z92981; CAB07505.1; JOINED; Genomic_DNA.
DR EMBL; AF060913; AAD28355.1; -; Genomic_DNA.
DR EMBL; AF060910; AAD28355.1; JOINED; Genomic_DNA.
DR EMBL; AF060911; AAD28355.1; JOINED; Genomic_DNA.
DR EMBL; AF060912; AAD28355.1; JOINED; Genomic_DNA.
DR EMBL; DQ402522; ABD72218.1; -; mRNA.
DR EMBL; AK304379; BAG65217.1; -; mRNA.
DR EMBL; FJ515830; ACS13721.1; -; Genomic_DNA.
DR EMBL; AC005840; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC006057; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471116; EAW88804.1; -; Genomic_DNA.
DR EMBL; BC006526; AAH06526.2; ALT_INIT; mRNA.
DR EMBL; BC062613; AAH62613.1; -; mRNA.
DR EMBL; U81961; AAC31773.1; -; Genomic_DNA.
DR EMBL; U81961; AAC31774.1; -; Genomic_DNA.
DR CCDS; CCDS53738.1; -. [P37088-2]
DR CCDS; CCDS53739.1; -. [P37088-6]
DR CCDS; CCDS8543.1; -. [P37088-1]
DR PIR; A49585; A49585.
DR RefSeq; NP_001029.1; NM_001038.5. [P37088-1]
DR RefSeq; NP_001153047.1; NM_001159575.1. [P37088-6]
DR RefSeq; NP_001153048.1; NM_001159576.1. [P37088-2]
DR PDB; 2M3O; NMR; -; P=638-648.
DR PDB; 6BQN; EM; 3.90 A; A=111-543.
DR PDB; 6WTH; EM; 3.06 A; A=1-669.
DR PDBsum; 2M3O; -.
DR PDBsum; 6BQN; -.
DR PDBsum; 6WTH; -.
DR AlphaFoldDB; P37088; -.
DR SMR; P37088; -.
DR BioGRID; 112241; 101.
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 CORUM; P37088; -.
DR ELM; P37088; -.
DR IntAct; P37088; 4.
DR MINT; P37088; -.
DR STRING; 9606.ENSP00000353292; -.
DR BindingDB; P37088; -.
DR ChEMBL; CHEMBL1791; -.
DR DrugBank; DB00594; Amiloride.
DR DrugBank; DB14509; Lithium carbonate.
DR DrugBank; DB00384; Triamterene.
DR DrugCentral; P37088; -.
DR GuidetoPHARMACOLOGY; 738; -.
DR TCDB; 1.A.6.1.1; the epithelial na(+) channel (enac) family.
DR iPTMnet; P37088; -.
DR PhosphoSitePlus; P37088; -.
DR BioMuta; SCNN1A; -.
DR DMDM; 585966; -.
DR EPD; P37088; -.
DR jPOST; P37088; -.
DR MassIVE; P37088; -.
DR PaxDb; P37088; -.
DR PeptideAtlas; P37088; -.
DR PRIDE; P37088; -.
DR ProteomicsDB; 55257; -. [P37088-1]
DR ProteomicsDB; 55258; -. [P37088-2]
DR ProteomicsDB; 55259; -. [P37088-3]
DR ProteomicsDB; 55260; -. [P37088-4]
DR ProteomicsDB; 55261; -. [P37088-5]
DR ProteomicsDB; 55262; -. [P37088-6]
DR Antibodypedia; 2337; 330 antibodies from 34 providers.
DR DNASU; 6337; -.
DR Ensembl; ENST00000228916.7; ENSP00000228916.2; ENSG00000111319.13. [P37088-1]
DR Ensembl; ENST00000360168.7; ENSP00000353292.3; ENSG00000111319.13. [P37088-2]
DR Ensembl; ENST00000543768.1; ENSP00000438739.1; ENSG00000111319.13. [P37088-6]
DR GeneID; 6337; -.
DR KEGG; hsa:6337; -.
DR MANE-Select; ENST00000228916.7; ENSP00000228916.2; NM_001038.6; NP_001029.1.
DR UCSC; uc001qnw.3; human. [P37088-1]
DR CTD; 6337; -.
DR DisGeNET; 6337; -.
DR GeneCards; SCNN1A; -.
DR HGNC; HGNC:10599; SCNN1A.
DR HPA; ENSG00000111319; Tissue enhanced (salivary).
DR MalaCards; SCNN1A; -.
DR MIM; 264350; phenotype.
DR MIM; 600228; gene.
DR MIM; 613021; phenotype.
DR MIM; 618126; phenotype.
DR neXtProt; NX_P37088; -.
DR OpenTargets; ENSG00000111319; -.
DR Orphanet; 130; Brugada syndrome.
DR Orphanet; 171876; Generalized pseudohypoaldosteronism type 1.
DR Orphanet; 60033; Idiopathic bronchiectasis.
DR Orphanet; 526; Liddle syndrome.
DR PharmGKB; PA305; -.
DR VEuPathDB; HostDB:ENSG00000111319; -.
DR eggNOG; KOG4294; Eukaryota.
DR GeneTree; ENSGT00940000160952; -.
DR HOGENOM; CLU_020415_0_1_1; -.
DR InParanoid; P37088; -.
DR OMA; EKTRQCK; -.
DR OrthoDB; 686369at2759; -.
DR PhylomeDB; P37088; -.
DR TreeFam; TF330663; -.
DR PathwayCommons; P37088; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR Reactome; R-HSA-9730628; Sensory perception of salty taste.
DR SignaLink; P37088; -.
DR SIGNOR; P37088; -.
DR BioGRID-ORCS; 6337; 8 hits in 1069 CRISPR screens.
DR ChiTaRS; SCNN1A; human.
DR GeneWiki; SCNN1A; -.
DR GenomeRNAi; 6337; -.
DR Pharos; P37088; Tclin.
DR PRO; PR:P37088; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; P37088; protein.
DR Bgee; ENSG00000111319; Expressed in nasal cavity epithelium and 198 other tissues.
DR ExpressionAtlas; P37088; baseline and differential.
DR Genevisible; P37088; HS.
DR GO; GO:0001669; C:acrosomal vesicle; ISS:UniProtKB.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0060170; C:ciliary membrane; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0031514; C:motile cilium; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0034706; C:sodium channel complex; IDA:UniProtKB.
DR GO; GO:0097228; C:sperm principal piece; ISS:UniProtKB.
DR GO; GO:0015280; F:ligand-gated sodium channel activity; IEA:InterPro.
DR GO; GO:0050699; F:WW domain binding; IPI:BHF-UCL.
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:0050891; P:multicellular organismal water homeostasis; IDA:UniProtKB.
DR GO; GO:0008217; P:regulation of blood pressure; IC:ComplexPortal.
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 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; Cell projection; Cilium;
KW Cytoplasm; Cytoplasmic vesicle; Disease variant; Flagellum; Glycoprotein;
KW Ion channel; Ion transport; Membrane; Reference proteome;
KW Sensory transduction; Sodium; Sodium channel; Sodium transport; Taste;
KW Transmembrane; Transmembrane helix; Transport; Ubl conjugation.
FT CHAIN 1..669
FT /note="Amiloride-sensitive sodium channel subunit alpha"
FT /id="PRO_0000181261"
FT TOPO_DOM 1..85
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P37089"
FT TRANSMEM 86..106
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 107..562
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P37089"
FT TRANSMEM 563..583
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 584..669
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P37089"
FT REGION 1..43
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 620..669
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 633..648
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 1
FT /note="M -> MGMARGSLTRVPGVMGEGTQGPELSLDPDPCSPQSTPGLMKGNKLEE
FT QDPRPLQPIPGLM (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_007719"
FT VAR_SEQ 1
FT /note="M -> MSSIKGNKLEEQDPRPLQPIPGLM (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043667"
FT VAR_SEQ 229..245
FT /note="CNQNKSDCFYQTYSSGV -> ELLSLPPPDVWKLLYFG (in isoform
FT 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_007720"
FT VAR_SEQ 246..669
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_007721"
FT VAR_SEQ 327..345
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_007722"
FT VAR_SEQ 454
FT /note="G -> GQVRSLTPVIPALWEAEAGGSRG (in isoform 5)"
FT /evidence="ECO:0000305"
FT /id="VSP_007723"
FT VARIANT 61
FT /note="F -> L (in BESC2; hypoactive mutation resulting in
FT reduction of protein expression and a significant decrease
FT of amiloride-sensitive sodium currents; dbSNP:rs61758859)"
FT /evidence="ECO:0000269|PubMed:19462466"
FT /id="VAR_060793"
FT VARIANT 114
FT /note="V -> I (in BESC2; hyperactive mutation resulting in
FT a significant increase of amiloride-sensitive sodium
FT currents; dbSNP:rs61759861)"
FT /evidence="ECO:0000269|PubMed:19462466"
FT /id="VAR_060794"
FT VARIANT 181
FT /note="R -> W (significant increase of amiloride-sensitive
FT sodium currents; dbSNP:rs55797039)"
FT /evidence="ECO:0000269|PubMed:16207733,
FT ECO:0000269|PubMed:19462466"
FT /id="VAR_060795"
FT VARIANT 327
FT /note="G -> C (in PHA1B; results in a significant reduction
FT of channel function as compared to wild-type; significantly
FT lowers both Li+ and Na+ ion currents; dbSNP:rs974854786)"
FT /evidence="ECO:0000269|PubMed:15853823,
FT ECO:0000269|PubMed:18634878"
FT /id="VAR_026518"
FT VARIANT 334
FT /note="A -> T (significant decrease of amiloride-sensitive
FT sodium currents; dbSNP:rs11542844)"
FT /evidence="ECO:0000269|PubMed:10523338,
FT ECO:0000269|PubMed:19462466"
FT /id="VAR_060796"
FT VARIANT 402
FT /note="P -> H (in dbSNP:rs13306616)"
FT /id="VAR_052035"
FT VARIANT 479
FT /note="C -> R (in LIDLS3; increased channel activity;
FT dbSNP:rs201873521)"
FT /evidence="ECO:0000269|PubMed:28710092"
FT /id="VAR_081179"
FT VARIANT 493
FT /note="W -> R (results in a 4-fold increase of amiloride-
FT sensitive sodium currents; found in BESC2 patients at
FT higher frequency than in controls; associated with an
FT increased risk for ischemic cerebrovascular events;
FT dbSNP:rs5742912)"
FT /evidence="ECO:0000269|PubMed:10586178,
FT ECO:0000269|PubMed:19462466"
FT /id="VAR_015833"
FT VARIANT 562
FT /note="S -> L (in PHA1B; dbSNP:rs137852635)"
FT /evidence="ECO:0000269|PubMed:10586178"
FT /id="VAR_015834"
FT VARIANT 573
FT /note="V -> I (in dbSNP:rs59142484)"
FT /id="VAR_060797"
FT VARIANT 618
FT /note="C -> F (in dbSNP:rs3741913)"
FT /evidence="ECO:0000269|PubMed:10523338"
FT /id="VAR_022142"
FT VARIANT 663
FT /note="T -> A (in dbSNP:rs2228576)"
FT /evidence="ECO:0000269|PubMed:10404817,
FT ECO:0000269|PubMed:10523338, ECO:0000269|PubMed:12107247,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:15734793,
FT ECO:0000269|PubMed:17766193, ECO:0000269|PubMed:19462466"
FT /id="VAR_015835"
FT MUTAGEN 394
FT /note="C->S: Increased channel activity."
FT /evidence="ECO:0000269|PubMed:28710092"
FT STRAND 115..121
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 129..136
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 144..161
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 188..190
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 224..228
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 231..233
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 237..243
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 244..260
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 274..278
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 279..284
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 294..298
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 300..302
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 304..309
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 327..332
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 341..343
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 348..354
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 356..358
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 362..365
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 367..369
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 373..385
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 389..391
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 395..401
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 407..409
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 413..429
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 430..432
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 447..449
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 454..465
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 471..474
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 478..494
FT /evidence="ECO:0007829|PDB:6WTH"
FT TURN 496..498
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 499..509
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 522..529
FT /evidence="ECO:0007829|PDB:6WTH"
FT STRAND 531..539
FT /evidence="ECO:0007829|PDB:6WTH"
FT HELIX 644..647
FT /evidence="ECO:0007829|PDB:2M3O"
SQ SEQUENCE 669 AA; 75704 MW; 2CCF342E7DF32E72 CRC64;
MEGNKLEEQD SSPPQSTPGL MKGNKREEQG LGPEPAAPQQ PTAEEEALIE FHRSYRELFE
FFCNNTTIHG AIRLVCSQHN RMKTAFWAVL WLCTFGMMYW QFGLLFGEYF SYPVSLNINL
NSDKLVFPAV TICTLNPYRY PEIKEELEEL DRITEQTLFD LYKYSSFTTL VAGSRSRRDL
RGTLPHPLQR LRVPPPPHGA RRARSVASSL RDNNPQVDWK DWKIGFQLCN QNKSDCFYQT
YSSGVDAVRE WYRFHYINIL SRLPETLPSL EEDTLGNFIF ACRFNQVSCN QANYSHFHHP
MYGNCYTFND KNNSNLWMSS MPGINNGLSL MLRAEQNDFI PLLSTVTGAR VMVHGQDEPA
FMDDGGFNLR PGVETSISMR KETLDRLGGD YGDCTKNGSD VPVENLYPSK YTQQVCIHSC
FQESMIKECG CAYIFYPRPQ NVEYCDYRKH SSWGYCYYKL QVDFSSDHLG CFTKCRKPCS
VTSYQLSAGY SRWPSVTSQE WVFQMLSRQN NYTVNNKRNG VAKVNIFFKE LNYKTNSESP
SVTMVTLLSN LGSQWSLWFG SSVLSVVEMA ELVFDLLVIM FLMLLRRFRS RYWSPGRGGR
GAQEVASTLA SSPPSHFCPH PMSLSLSQPG PAPSPALTAP PPAYATLGPR PSPGGSAGAS
SSTCPLGGP
