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P55017

- S12A3_HUMAN

UniProt

P55017 - S12A3_HUMAN

Protein

Solute carrier family 12 member 3

Gene

SLC12A3

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 138 (01 Oct 2014)
      Sequence version 3 (30 Nov 2010)
      Previous versions | rss
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    Functioni

    Key mediator of sodium and chloride reabsorption in this nephron segment, accounting for a significant fraction of renal sodium reabsorption.1 Publication

    Enzyme regulationi

    Activated by WNK3.1 Publication

    GO - Molecular functioni

    1. protein binding Source: UniProtKB
    2. sodium:chloride symporter activity Source: ProtInc
    3. transporter activity Source: UniProtKB

    GO - Biological processi

    1. chloride transmembrane transport Source: GOC
    2. chloride transport Source: GOC
    3. ion transport Source: Reactome
    4. sodium ion transmembrane transport Source: BHF-UCL
    5. sodium ion transport Source: UniProtKB
    6. transmembrane transport Source: Reactome
    7. transport Source: ProtInc

    Keywords - Biological processi

    Ion transport, Sodium transport, Symport, Transport

    Keywords - Ligandi

    Sodium

    Enzyme and pathway databases

    ReactomeiREACT_19315. Cation-coupled Chloride cotransporters.

    Protein family/group databases

    TCDBi2.A.30.4.2. the cation-chloride cotransporter (ccc) family.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Solute carrier family 12 member 3
    Alternative name(s):
    Na-Cl cotransporter
    Short name:
    NCC
    Na-Cl symporter
    Thiazide-sensitive sodium-chloride cotransporter
    Gene namesi
    Name:SLC12A3
    Synonyms:NCC, TSC
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 16

    Organism-specific databases

    HGNCiHGNC:10912. SLC12A3.

    Subcellular locationi

    GO - Cellular componenti

    1. apical plasma membrane Source: UniProtKB
    2. cytosol Source: Ensembl
    3. extracellular vesicular exosome Source: UniProtKB
    4. integral component of plasma membrane Source: ProtInc
    5. membrane Source: ProtInc
    6. plasma membrane Source: Reactome

    Keywords - Cellular componenti

    Cell membrane, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Gitelman syndrome (GS) [MIM:263800]: An autosomal recessive disorder characterized by hypokalemic alkalosis in combination with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. Patients are often asymptomatic or present transient periods of muscular weakness and tetany, usually accompanied by abdominal pain, vomiting and fever. The phenotype is highly heterogeneous in terms of age at onset and severity. Cardinal features such as hypocalciuria and hypomagnesemia might also change during the life cycle of a given patient. It has overlapping features with Bartter syndrome.15 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti60 – 601T → M in GS. 1 Publication
    VAR_039475
    Natural varianti62 – 621D → N in GS. 1 Publication
    VAR_039476
    Natural varianti68 – 681E → K in GS. 1 Publication
    VAR_039477
    Natural varianti69 – 691H → N in GS. 1 Publication
    VAR_039478
    Natural varianti90 – 901H → Y in GS. 1 Publication
    VAR_039479
    Natural varianti145 – 1451R → H in GS. 1 Publication
    VAR_039480
    Natural varianti153 – 1531V → M in GS. 1 Publication
    VAR_039481
    Natural varianti154 – 1541I → F in GS. 1 Publication
    VAR_039482
    Natural varianti158 – 1581R → Q in GS. 1 Publication
    VAR_039483
    Natural varianti163 – 1631T → M in GS. 1 Publication
    VAR_039484
    Natural varianti172 – 1721W → R in GS. 1 Publication
    VAR_039485
    Natural varianti178 – 1781S → L in GS. 1 Publication
    VAR_039486
    Natural varianti180 – 1801T → K in GS. 1 Publication
    Corresponds to variant rs146158333 [ dbSNP | Ensembl ].
    VAR_039487
    Natural varianti186 – 1861G → D in GS. 1 Publication
    VAR_039488
    Natural varianti209 – 2091R → Q in GS. 1 Publication
    Corresponds to variant rs28936388 [ dbSNP | Ensembl ].
    VAR_039489
    Natural varianti209 – 2091R → W in GS. 4 Publications
    Corresponds to variant rs28936388 [ dbSNP | Ensembl ].
    VAR_007113
    Natural varianti215 – 2151L → P in GS. 1 Publication
    VAR_039490
    Natural varianti226 – 2261A → T in GS. 1 Publication
    VAR_039491
    Natural varianti230 – 2301G → D in GS. 1 Publication
    VAR_039492
    Natural varianti261 – 2611R → H in GS. 1 Publication
    VAR_039493
    Natural varianti283 – 2831S → Y in GS. 1 Publication
    VAR_039495
    Natural varianti284 – 2841K → R in GS. 1 Publication
    VAR_039496
    Natural varianti304 – 3041T → P in GS. 1 Publication
    VAR_039497
    Natural varianti313 – 3131A → V in GS. 1 Publication
    VAR_039498
    Natural varianti316 – 3161G → V in GS. 1 Publication
    VAR_039499
    Natural varianti321 – 3211R → W in GS. 1 Publication
    VAR_039500
    Natural varianti334 – 3341R → W in GS. 1 Publication
    VAR_039501
    Natural varianti342 – 3421G → A in GS. 1 Publication
    VAR_039502
    Natural varianti349 – 3491P → L in GS. 2 Publications
    VAR_007114
    Natural varianti374 – 3741G → V in GS. 1 Publication
    VAR_039503
    Natural varianti399 – 3991R → C in GS. 1 Publication
    VAR_039504
    Natural varianti421 – 4211C → R in GS. 1 Publication
    Corresponds to variant rs28936387 [ dbSNP | Ensembl ].
    VAR_007115
    Natural varianti439 – 4391G → S in GS. 2 Publications
    VAR_039505
    Natural varianti463 – 4631G → E in GS. 1 Publication
    VAR_039506
    Natural varianti464 – 4641A → T in GS. 1 Publication
    VAR_039507
    Natural varianti478 – 4781K → E in GS. 1 Publication
    VAR_039508
    Natural varianti486 – 4861D → N in GS. 2 Publications
    VAR_007116
    Natural varianti496 – 4961G → C in GS. 2 Publications
    VAR_007117
    Natural varianti542 – 5421L → P in GS. 1 Publication
    VAR_039509
    Natural varianti555 – 5551S → L in GS. 1 Publication
    VAR_039510
    Natural varianti560 – 5601P → H in GS. 1 Publication
    VAR_039511
    Natural varianti561 – 5611Missing in GS. 1 Publication
    VAR_007118
    Natural varianti569 – 5691A → E in GS. 1 Publication
    VAR_039512
    Natural varianti569 – 5691A → V in GS. 1 Publication
    VAR_039513
    Natural varianti578 – 5781V → M in GS. 1 Publication
    Corresponds to variant rs139329616 [ dbSNP | Ensembl ].
    VAR_039514
    Natural varianti588 – 5881A → V in GS. 2 Publications
    VAR_007119
    Natural varianti613 – 6131G → S in GS. 1 Publication
    VAR_039515
    Natural varianti615 – 6151S → L in GS. 2 Publications
    VAR_039516
    Natural varianti615 – 6151S → W in GS. 1 Publication
    VAR_039517
    Natural varianti623 – 6231L → P in GS. 2 Publications
    VAR_039518
    Natural varianti630 – 6301G → V in GS. 1 Publication
    Corresponds to variant rs28936389 [ dbSNP | Ensembl ].
    VAR_007120
    Natural varianti642 – 6421R → C in GS. 2 Publications
    Corresponds to variant rs200697179 [ dbSNP | Ensembl ].
    VAR_039519
    Natural varianti642 – 6421R → G in GS. 2 Publications
    VAR_039520
    Natural varianti642 – 6421R → H in GS. 2 Publications
    VAR_039521
    Natural varianti643 – 6431P → L in GS. 2 Publications
    Corresponds to variant rs140012781 [ dbSNP | Ensembl ].
    VAR_039522
    Natural varianti649 – 6491T → R in GS. 1 Publication
    VAR_039523
    Natural varianti655 – 6551R → C in GS. 1 Publication
    VAR_039524
    Natural varianti655 – 6551R → H in GS. 1 Publication
    VAR_007121
    Natural varianti655 – 6551R → L in GS. 1 Publication
    VAR_007122
    Natural varianti672 – 6721M → I in GS. 1 Publication
    VAR_039525
    Natural varianti677 – 6771V → L in GS. 1 Publication
    VAR_039526
    Natural varianti677 – 6771V → M in GS. 1 Publication
    VAR_039527
    Natural varianti729 – 7291G → V in GS. 1 Publication
    VAR_039528
    Natural varianti731 – 7311G → R in GS. 2 Publications
    VAR_039529
    Natural varianti738 – 7381L → R in GS. 1 Publication
    VAR_039530
    Natural varianti741 – 7411G → R in GS. 3 Publications
    Corresponds to variant rs138977195 [ dbSNP | Ensembl ].
    VAR_007124
    Natural varianti849 – 8491L → H in GS. 3 Publications
    Corresponds to variant rs185927948 [ dbSNP | Ensembl ].
    VAR_039531
    Natural varianti850 – 8501L → P in GS. 2 Publications
    VAR_007125
    Natural varianti852 – 8521R → C in GS. 2 Publications
    VAR_039532
    Natural varianti852 – 8521R → H in GS. 1 Publication
    VAR_039533
    Natural varianti852 – 8521R → S in GS. 1 Publication
    VAR_039534
    Natural varianti867 – 8671G → S in GS. 1 Publication
    VAR_039535
    Natural varianti871 – 8711R → H in GS. 1 Publication
    VAR_039536
    Natural varianti955 – 9551R → Q in GS. 1 Publication
    VAR_007126
    Natural varianti958 – 9581R → G in GS. 1 Publication
    VAR_039539
    Natural varianti985 – 9851C → Y in GS. 1 Publication
    Corresponds to variant rs199849117 [ dbSNP | Ensembl ].
    VAR_039540

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    MIMi263800. phenotype.
    Orphaneti358. Gitelman syndrome.
    PharmGKBiPA321.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 10211021Solute carrier family 12 member 3PRO_0000178026Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Glycosylationi406 – 4061N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi426 – 4261N-linked (GlcNAc...)Sequence Analysis

    Post-translational modificationi

    Ubiquitinated; ubiquitination is essential for regulation of endocytosis. The BCR(KLHL3) complex was initially identified as a candidate ubiquitin ligase for SLC12A3 (PubMed:22406640). However, it was later shown that it is not the case.1 Publication

    Keywords - PTMi

    Glycoprotein, Ubl conjugation

    Proteomic databases

    PaxDbiP55017.
    PRIDEiP55017.

    PTM databases

    PhosphoSiteiP55017.

    Expressioni

    Tissue specificityi

    Predominant in kidney.

    Gene expression databases

    ArrayExpressiP55017.
    BgeeiP55017.
    CleanExiHS_SLC12A3.
    GenevestigatoriP55017.

    Organism-specific databases

    HPAiCAB022505.
    HPA028748.

    Interactioni

    Subunit structurei

    Interacts with KLHL3.1 Publication

    Protein-protein interaction databases

    BioGridi112448. 11 interactions.
    STRINGi9606.ENSP00000262502.

    Structurei

    3D structure databases

    ProteinModelPortaliP55017.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 135135CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini180 – 21839CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini283 – 2864CytoplasmicSequence Analysis
    Topological domaini361 – 37717CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini474 – 51138CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini556 – 57722CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini682 – 1021340CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei136 – 15621HelicalSequence AnalysisAdd
    BLAST
    Transmembranei159 – 17921HelicalSequence AnalysisAdd
    BLAST
    Transmembranei219 – 23921HelicalSequence AnalysisAdd
    BLAST
    Transmembranei262 – 28221HelicalSequence AnalysisAdd
    BLAST
    Transmembranei287 – 30721HelicalSequence AnalysisAdd
    BLAST
    Transmembranei340 – 36021HelicalSequence AnalysisAdd
    BLAST
    Transmembranei378 – 39821HelicalSequence AnalysisAdd
    BLAST
    Transmembranei453 – 47321HelicalSequence AnalysisAdd
    BLAST
    Transmembranei512 – 53221HelicalSequence AnalysisAdd
    BLAST
    Transmembranei535 – 55521HelicalSequence AnalysisAdd
    BLAST
    Transmembranei578 – 59821HelicalSequence AnalysisAdd
    BLAST
    Transmembranei661 – 68121HelicalSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the SLC12A transporter family.Curated

    Keywords - Domaini

    Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiCOG0531.
    HOGENOMiHOG000062855.
    HOVERGENiHBG052851.
    InParanoidiP55017.
    KOiK14426.
    OMAiQLYPLIG.
    OrthoDBiEOG75MVVC.
    PhylomeDBiP55017.
    TreeFamiTF313191.

    Family and domain databases

    InterProiIPR004841. AA-permease/SLC12A_dom.
    IPR013612. AA_permease_N.
    IPR004842. Na/K/Cl_cotransptS.
    IPR002948. NaCl_cotranspt.
    [Graphical view]
    PfamiPF00324. AA_permease. 1 hit.
    PF08403. AA_permease_N. 1 hit.
    [Graphical view]
    PRINTSiPR01230. NACLTRNSPORT.
    TIGRFAMsiTIGR00930. 2a30. 1 hit.

    Sequences (3)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P55017-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST     50
    FCMRTFGYNT IDVVPTYEHY ANSTQPGEPR KVRPTLADLH SFLKQEGRHL 100
    HALAFDSRPS HEMTDGLVEG EAGTSSEKNP EEPVRFGWVK GVMIRCMLNI 150
    WGVILYLRLP WITAQAGIVL TWIIILLSVT VTSITGLSIS AISTNGKVKS 200
    GGTYFLISRS LGPELGGSIG LIFAFANAVG VAMHTVGFAE TVRDLLQEYG 250
    APIVDPINDI RIIAVVSVTV LLAISLAGME WESKAQVLFF LVIMVSFANY 300
    LVGTLIPPSE DKASKGFFSY RADIFVQNLV PDWRGPDGTF FGMFSIFFPS 350
    ATGILAGANI SGDLKDPAIA IPKGTLMAIF WTTISYLAIS ATIGSCVVRD 400
    ASGVLNDTVT PGWGACEGLA CSYGWNFTEC TQQHSCHYGL INYYQTMSMV 450
    SGFAPLITAG IFGATLSSAL ACLVSAAKVF QCLCEDQLYP LIGFFGKGYG 500
    KNKEPVRGYL LAYAIAVAFI IIAELNTIAP IISNFFLCSY ALINFSCFHA 550
    SITNSPGWRP SFQYYNKWAA LFGAIISVVI MFLLTWWAAL IAIGVVLFLL 600
    LYVIYKKPEV NWGSSVQAGS YNLALSYSVG LNEVEDHIKN YRPQCLVLTG 650
    PPNFRPALVD FVGTFTRNLS LMICGHVLIG PHKQRMPELQ LIANGHTKWL 700
    NKRKIKAFYS DVIAEDLRRG VQILMQAAGL GRMKPNILVV GFKKNWQSAH 750
    PATVEDYIGI LHDAFDFNYG VCVMRMREGL NVSKMMQAHI NPVFDPAEDG 800
    KEASARVDPK ALVKEEQATT IFQSEQGKKT IDIYWLFDDG GLTLLIPYLL 850
    GRKRRWSKCK IRVFVGGQIN RMDQERKAII SLLSKFRLGF HEVHILPDIN 900
    QNPRAEHTKR FEDMIAPFRL NDGFKDEATV NEMRRDCPWK ISDEEITKNR 950
    VKSLRQVRLN EIVLDYSRDA ALIVITLPIG RKGKCPSSLY MAWLETLSQD 1000
    LRPPVILIRG NQENVLTFYC Q 1021
    Length:1,021
    Mass (Da):113,139
    Last modified:November 30, 2010 - v3
    Checksum:i629C5A42F3234B71
    GO
    Isoform 2 (identifier: P55017-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         807-807: V → GARPSVSGAL

    Show »
    Length:1,030
    Mass (Da):113,936
    Checksum:i5CB36A5FF81494A3
    GO
    Isoform 3 (identifier: P55017-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         95-95: Missing.
         807-807: V → GARPSVSGAL

    Note: No experimental confirmation available.

    Show »
    Length:1,029
    Mass (Da):113,808
    Checksum:iDD190B2391AE0525
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti459 – 4602AG → VV in CAA62613. (PubMed:8812482)Curated
    Sequence conflicti539 – 5391S → P in AK315298. (PubMed:14702039)Curated
    Sequence conflicti766 – 7661D → E in AAC50355. (PubMed:8528245)Curated
    Sequence conflicti778 – 7781Missing in AK315298. (PubMed:14702039)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti60 – 601T → M in GS. 1 Publication
    VAR_039475
    Natural varianti62 – 621D → N in GS. 1 Publication
    VAR_039476
    Natural varianti68 – 681E → K in GS. 1 Publication
    VAR_039477
    Natural varianti69 – 691H → N in GS. 1 Publication
    VAR_039478
    Natural varianti90 – 901H → Y in GS. 1 Publication
    VAR_039479
    Natural varianti145 – 1451R → H in GS. 1 Publication
    VAR_039480
    Natural varianti153 – 1531V → M in GS. 1 Publication
    VAR_039481
    Natural varianti154 – 1541I → F in GS. 1 Publication
    VAR_039482
    Natural varianti158 – 1581R → Q in GS. 1 Publication
    VAR_039483
    Natural varianti163 – 1631T → M in GS. 1 Publication
    VAR_039484
    Natural varianti172 – 1721W → R in GS. 1 Publication
    VAR_039485
    Natural varianti178 – 1781S → L in GS. 1 Publication
    VAR_039486
    Natural varianti180 – 1801T → K in GS. 1 Publication
    Corresponds to variant rs146158333 [ dbSNP | Ensembl ].
    VAR_039487
    Natural varianti186 – 1861G → D in GS. 1 Publication
    VAR_039488
    Natural varianti209 – 2091R → Q in GS. 1 Publication
    Corresponds to variant rs28936388 [ dbSNP | Ensembl ].
    VAR_039489
    Natural varianti209 – 2091R → W in GS. 4 Publications
    Corresponds to variant rs28936388 [ dbSNP | Ensembl ].
    VAR_007113
    Natural varianti215 – 2151L → P in GS. 1 Publication
    VAR_039490
    Natural varianti226 – 2261A → T in GS. 1 Publication
    VAR_039491
    Natural varianti230 – 2301G → D in GS. 1 Publication
    VAR_039492
    Natural varianti261 – 2611R → H in GS. 1 Publication
    VAR_039493
    Natural varianti264 – 2641A → G.5 Publications
    Corresponds to variant rs1529927 [ dbSNP | Ensembl ].
    VAR_039494
    Natural varianti283 – 2831S → Y in GS. 1 Publication
    VAR_039495
    Natural varianti284 – 2841K → R in GS. 1 Publication
    VAR_039496
    Natural varianti304 – 3041T → P in GS. 1 Publication
    VAR_039497
    Natural varianti313 – 3131A → V in GS. 1 Publication
    VAR_039498
    Natural varianti316 – 3161G → V in GS. 1 Publication
    VAR_039499
    Natural varianti321 – 3211R → W in GS. 1 Publication
    VAR_039500
    Natural varianti334 – 3341R → W in GS. 1 Publication
    VAR_039501
    Natural varianti342 – 3421G → A in GS. 1 Publication
    VAR_039502
    Natural varianti349 – 3491P → L in GS. 2 Publications
    VAR_007114
    Natural varianti374 – 3741G → V in GS. 1 Publication
    VAR_039503
    Natural varianti399 – 3991R → C in GS. 1 Publication
    VAR_039504
    Natural varianti421 – 4211C → R in GS. 1 Publication
    Corresponds to variant rs28936387 [ dbSNP | Ensembl ].
    VAR_007115
    Natural varianti439 – 4391G → S in GS. 2 Publications
    VAR_039505
    Natural varianti463 – 4631G → E in GS. 1 Publication
    VAR_039506
    Natural varianti464 – 4641A → T in GS. 1 Publication
    VAR_039507
    Natural varianti478 – 4781K → E in GS. 1 Publication
    VAR_039508
    Natural varianti486 – 4861D → N in GS. 2 Publications
    VAR_007116
    Natural varianti496 – 4961G → C in GS. 2 Publications
    VAR_007117
    Natural varianti542 – 5421L → P in GS. 1 Publication
    VAR_039509
    Natural varianti555 – 5551S → L in GS. 1 Publication
    VAR_039510
    Natural varianti560 – 5601P → H in GS. 1 Publication
    VAR_039511
    Natural varianti561 – 5611Missing in GS. 1 Publication
    VAR_007118
    Natural varianti569 – 5691A → E in GS. 1 Publication
    VAR_039512
    Natural varianti569 – 5691A → V in GS. 1 Publication
    VAR_039513
    Natural varianti578 – 5781V → M in GS. 1 Publication
    Corresponds to variant rs139329616 [ dbSNP | Ensembl ].
    VAR_039514
    Natural varianti588 – 5881A → V in GS. 2 Publications
    VAR_007119
    Natural varianti613 – 6131G → S in GS. 1 Publication
    VAR_039515
    Natural varianti615 – 6151S → L in GS. 2 Publications
    VAR_039516
    Natural varianti615 – 6151S → W in GS. 1 Publication
    VAR_039517
    Natural varianti623 – 6231L → P in GS. 2 Publications
    VAR_039518
    Natural varianti630 – 6301G → V in GS. 1 Publication
    Corresponds to variant rs28936389 [ dbSNP | Ensembl ].
    VAR_007120
    Natural varianti642 – 6421R → C in GS. 2 Publications
    Corresponds to variant rs200697179 [ dbSNP | Ensembl ].
    VAR_039519
    Natural varianti642 – 6421R → G in GS. 2 Publications
    VAR_039520
    Natural varianti642 – 6421R → H in GS. 2 Publications
    VAR_039521
    Natural varianti643 – 6431P → L in GS. 2 Publications
    Corresponds to variant rs140012781 [ dbSNP | Ensembl ].
    VAR_039522
    Natural varianti649 – 6491T → R in GS. 1 Publication
    VAR_039523
    Natural varianti655 – 6551R → C in GS. 1 Publication
    VAR_039524
    Natural varianti655 – 6551R → H in GS. 1 Publication
    VAR_007121
    Natural varianti655 – 6551R → L in GS. 1 Publication
    VAR_007122
    Natural varianti672 – 6721M → I in GS. 1 Publication
    VAR_039525
    Natural varianti677 – 6771V → L in GS. 1 Publication
    VAR_039526
    Natural varianti677 – 6771V → M in GS. 1 Publication
    VAR_039527
    Natural varianti728 – 7281A → T.2 Publications
    Corresponds to variant rs36049418 [ dbSNP | Ensembl ].
    VAR_007123
    Natural varianti729 – 7291G → V in GS. 1 Publication
    VAR_039528
    Natural varianti731 – 7311G → R in GS. 2 Publications
    VAR_039529
    Natural varianti738 – 7381L → R in GS. 1 Publication
    VAR_039530
    Natural varianti741 – 7411G → R in GS. 3 Publications
    Corresponds to variant rs138977195 [ dbSNP | Ensembl ].
    VAR_007124
    Natural varianti849 – 8491L → H in GS. 3 Publications
    Corresponds to variant rs185927948 [ dbSNP | Ensembl ].
    VAR_039531
    Natural varianti850 – 8501L → P in GS. 2 Publications
    VAR_007125
    Natural varianti852 – 8521R → C in GS. 2 Publications
    VAR_039532
    Natural varianti852 – 8521R → H in GS. 1 Publication
    VAR_039533
    Natural varianti852 – 8521R → S in GS. 1 Publication
    VAR_039534
    Natural varianti854 – 8541R → K.
    Corresponds to variant rs8060046 [ dbSNP | Ensembl ].
    VAR_060106
    Natural varianti867 – 8671G → S in GS. 1 Publication
    VAR_039535
    Natural varianti871 – 8711R → H in GS. 1 Publication
    VAR_039536
    Natural varianti904 – 9041R → Q.4 Publications
    Corresponds to variant rs11643718 [ dbSNP | Ensembl ].
    VAR_039537
    Natural varianti919 – 9191R → C Increases sodium transport. 2 Publications
    Corresponds to variant rs12708965 [ dbSNP | Ensembl ].
    VAR_039538
    Natural varianti955 – 9551R → Q in GS. 1 Publication
    VAR_007126
    Natural varianti958 – 9581R → G in GS. 1 Publication
    VAR_039539
    Natural varianti985 – 9851C → Y in GS. 1 Publication
    Corresponds to variant rs199849117 [ dbSNP | Ensembl ].
    VAR_039540

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei95 – 951Missing in isoform 3. 1 PublicationVSP_040100
    Alternative sequencei807 – 8071V → GARPSVSGAL in isoform 2 and isoform 3. 2 PublicationsVSP_036318

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U44128 mRNA. Translation: AAC50355.1.
    X91220 mRNA. Translation: CAA62613.1.
    AK315298 mRNA. No translation available.
    AC012181 Genomic DNA. No translation available.
    CCDSiCCDS10770.1. [P55017-2]
    CCDS45491.1. [P55017-3]
    CCDS58464.1. [P55017-1]
    PIRiG01202.
    PC4180.
    RefSeqiNP_000330.2. NM_000339.2.
    NP_001119579.1. NM_001126107.1.
    NP_001119580.1. NM_001126108.1.
    UniGeneiHs.669115.

    Genome annotation databases

    EnsembliENST00000438926; ENSP00000402152; ENSG00000070915. [P55017-2]
    ENST00000563236; ENSP00000456149; ENSG00000070915. [P55017-1]
    ENST00000566786; ENSP00000457552; ENSG00000070915. [P55017-3]
    GeneIDi6559.
    KEGGihsa:6559.
    UCSCiuc002ekd.4. human. [P55017-2]
    uc010ccm.3. human. [P55017-1]
    uc010ccn.3. human. [P55017-3]

    Polymorphism databases

    DMDMi313104194.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U44128 mRNA. Translation: AAC50355.1 .
    X91220 mRNA. Translation: CAA62613.1 .
    AK315298 mRNA. No translation available.
    AC012181 Genomic DNA. No translation available.
    CCDSi CCDS10770.1. [P55017-2 ]
    CCDS45491.1. [P55017-3 ]
    CCDS58464.1. [P55017-1 ]
    PIRi G01202.
    PC4180.
    RefSeqi NP_000330.2. NM_000339.2.
    NP_001119579.1. NM_001126107.1.
    NP_001119580.1. NM_001126108.1.
    UniGenei Hs.669115.

    3D structure databases

    ProteinModelPortali P55017.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 112448. 11 interactions.
    STRINGi 9606.ENSP00000262502.

    Chemistry

    ChEMBLi CHEMBL1876.
    DrugBanki DB00436. Bendroflumethiazide.
    DB00562. Benzthiazide.
    DB00880. Chlorothiazide.
    DB01119. Diazoxide.
    DB00999. Hydrochlorothiazide.
    DB00524. Metolazone.
    DB01324. Polythiazide.
    DB01325. Quinethazone.
    GuidetoPHARMACOLOGYi 970.

    Protein family/group databases

    TCDBi 2.A.30.4.2. the cation-chloride cotransporter (ccc) family.

    PTM databases

    PhosphoSitei P55017.

    Polymorphism databases

    DMDMi 313104194.

    Proteomic databases

    PaxDbi P55017.
    PRIDEi P55017.

    Protocols and materials databases

    DNASUi 6559.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000438926 ; ENSP00000402152 ; ENSG00000070915 . [P55017-2 ]
    ENST00000563236 ; ENSP00000456149 ; ENSG00000070915 . [P55017-1 ]
    ENST00000566786 ; ENSP00000457552 ; ENSG00000070915 . [P55017-3 ]
    GeneIDi 6559.
    KEGGi hsa:6559.
    UCSCi uc002ekd.4. human. [P55017-2 ]
    uc010ccm.3. human. [P55017-1 ]
    uc010ccn.3. human. [P55017-3 ]

    Organism-specific databases

    CTDi 6559.
    GeneCardsi GC16P056899.
    HGNCi HGNC:10912. SLC12A3.
    HPAi CAB022505.
    HPA028748.
    MIMi 263800. phenotype.
    600968. gene.
    neXtProti NX_P55017.
    Orphaneti 358. Gitelman syndrome.
    PharmGKBi PA321.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0531.
    HOGENOMi HOG000062855.
    HOVERGENi HBG052851.
    InParanoidi P55017.
    KOi K14426.
    OMAi QLYPLIG.
    OrthoDBi EOG75MVVC.
    PhylomeDBi P55017.
    TreeFami TF313191.

    Enzyme and pathway databases

    Reactomei REACT_19315. Cation-coupled Chloride cotransporters.

    Miscellaneous databases

    GeneWikii Sodium-chloride_symporter.
    GenomeRNAii 6559.
    NextBioi 25523.
    PROi P55017.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P55017.
    Bgeei P55017.
    CleanExi HS_SLC12A3.
    Genevestigatori P55017.

    Family and domain databases

    InterProi IPR004841. AA-permease/SLC12A_dom.
    IPR013612. AA_permease_N.
    IPR004842. Na/K/Cl_cotransptS.
    IPR002948. NaCl_cotranspt.
    [Graphical view ]
    Pfami PF00324. AA_permease. 1 hit.
    PF08403. AA_permease_N. 1 hit.
    [Graphical view ]
    PRINTSi PR01230. NACLTRNSPORT.
    TIGRFAMsi TIGR00930. 2a30. 1 hit.
    ProtoNeti Search...

    Publicationsi

    1. "Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter."
      Simon D.B., Nelson-Williams C., Bia M.J., Ellison D., Karet F.E., Molina A.M., Vaara I., Iwata F., Cushner H.M., Koolen M., Gainza F.J., Gitelman H.J., Lifton R.P.
      Nat. Genet. 12:24-30(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), VARIANTS GS TRP-209; GLY-264; LEU-349; ARG-421; ASN-486; CYS-496; SER-561 DEL; VAL-588; VAL-630; HIS-655; LEU-655; ARG-741; PRO-850 AND GLN-955, VARIANT THR-728, FUNCTION.
    2. "Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3)."
      Mastroianni N., de Fusco M., Zollo M., Arrigo G., Zuffardi O., Bettinelli A., Ballabio A., Casari G.
      Genomics 35:486-493(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT GLY-264.
      Tissue: Kidney.
    3. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), VARIANT GLY-264.
    4. "The sequence and analysis of duplication-rich human chromosome 16."
      Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.
      , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A.
      Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    5. Cited for: ENZYME REGULATION.
    6. "Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome."
      Mastroianni N., Bettinelli A., Bianchetti M., Colussi G., De Fusco M., Sereni F., Ballabio A., Casari G.
      Am. J. Hum. Genet. 59:1019-1026(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS ASN-62; ASP-186; TRP-209; LEU-349; SER-439; GLU-478; ASN-486; CYS-496; PRO-542; VAL-588 AND ARG-731.
    7. Cited for: INTERACTION WITH KLHL3, UBIQUITINATION.
    8. "Association of a mutation in thiazide-sensitive Na-Cl cotransporter with familial Gitelman's syndrome."
      Takeuchi K., Kure S., Kato T., Taniyama Y., Takahashi N., Ikeda Y., Abe T., Narisawa K., Muramatsu Y., Abe K.
      J. Clin. Endocrinol. Metab. 81:4496-4499(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT GS PRO-623.
    9. "Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain."
      Lemmink H.H., Knoers N.V.A.M., Karolyi L., van Dijk H., Niaudet P., Antignac C., Guay-Woodford L.M., Goodyer P.R., Carel J.-C., Hermes A., Seyberth H.W., Monnens L.A.H., van den Heuvel L.P.W.J.
      Kidney Int. 54:720-730(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS TRP-209; PRO-215; THR-226; HIS-261; HIS-560; SER-613; HIS-642; ARG-649; CYS-655; ARG-738; ARG-741; PRO-850 AND CYS-852, VARIANTS GLN-904 AND CYS-919.
    10. "Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension."
      Melander O., Orho-Melander M., Bengtsson K., Lindblad U., Rastam L., Groop L., Hulthen U.L.
      Hypertension 36:389-394(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS PRO-304; SER-439; ARG-731 AND ARG-741, VARIANT GLN-904.
    11. "Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome."
      Monkawa T., Kurihara I., Kobayashi K., Hayashi M., Saruta T.
      J. Am. Soc. Nephrol. 11:65-70(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS LYS-180; GLU-569; MET-578; CYS-642 AND HIS-849.
    12. "Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life."
      Cruz D.N., Shaer A.J., Bia M.J., Lifton R.P., Simon D.B.
      Kidney Int. 59:710-717(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS PHE-154; LEU-178; GLN-209; ARG-284; VAL-313; TRP-321; TRP-334; CYS-399; LEU-555; LEU-615; GLY-642; LEU-643 AND VAL-729.
    13. "Severe hypomagnesaemia-induced hypocalcaemia in a patient with Gitelman's syndrome."
      Pantanetti P., Arnaldi G., Balercia G., Mantero F., Giacchetti G.
      Clin. Endocrinol. (Oxf.) 56:413-418(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT GS LEU-643, VARIANT GLY-264.
    14. "Two novel mutations of thiazide-sensitive Na-Cl cotrans porter (TSC) gene in two sporadic Japanese patients with Gitelman syndrome."
      Tajima T., Kobayashi Y., Abe S., Takahashi M., Konno M., Nakae J., Okuhara K., Satoh K., Ishikawa T., Imai T., Fujieda K.
      Endocr. J. 49:91-96(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT GS PRO-623.
    15. "Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome."
      Syren M.-L., Tedeschi S., Cesareo L., Bellantuono R., Colussi G., Procaccio M., Ali A., Domenici R., Malberti F., Sprocati M., Sacco M., Miglietti N., Edefonti A., Sereni F., Casari G., Coviello D.A., Bettinelli A.
      Hum. Mutat. 20:78-78(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS GLN-158; MET-163; ARG-172; TRP-209; VAL-316; VAL-374; GLU-463; THR-464; LEU-615; TRP-615; GLY-642; HIS-642; MET-677; CYS-852; SER-852; GLY-958 AND TYR-985, VARIANT GLN-904.
    16. "Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome."
      Maki N., Komatsuda A., Wakui H., Ohtani H., Kigawa A., Aiba N., Hamai K., Motegi M., Yamaguchi A., Imai H., Sawada K.
      Nephrol. Dial. Transplant. 19:1761-1766(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS MET-60; VAL-569; CYS-642 AND HIS-849.
    17. "Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome."
      Lin S.-H., Shiang J.-C., Huang C.-C., Yang S.-S., Hsu Y.-J., Cheng C.-J.
      J. Clin. Endocrinol. Metab. 90:2500-2507(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS TYR-90; TYR-283 AND HIS-871.
    18. "A novel mutation of the thiazide-sensitive sodium chloride cotransporter gene in a Japanese family with Gitelman syndrome."
      Terui K., Shoji M., Yamashiki J., Hirai Y., Ishiguro A., Tsutaya S., Kageyama K., Yasujima M., Suda T.
      Clin. Nephrol. 65:57-60(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT GS ILE-672.
    19. Cited for: VARIANTS GS LYS-68; ASN-69; HIS-145; MET-153; ASP-230; ALA-342; LEU-677 AND SER-867.
    20. "Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman's syndrome."
      Aoi N., Nakayama T., Tahira Y., Haketa A., Yabuki M., Sekiyama T., Nakane C., Mano H., Kawachi H., Sato N., Soma M., Matsumoto K.
      Endocrine 31:149-153(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GS HIS-849 AND HIS-852.
    21. "Molecular variants of the thiazide-sensitive Na+-Cl- cotransporter in hypertensive families."
      Keszei A.P., Tisler A., Backx P.H., Andrulis I.L., Bull S.B., Logan A.G.
      J. Hypertens. 25:2074-2081(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GLY-264; THR-728; GLN-904 AND CYS-919, CHARACTERIZATION OF VARIANT CYS-919.

    Entry informationi

    Entry nameiS12A3_HUMAN
    AccessioniPrimary (citable) accession number: P55017
    Secondary accession number(s): A8MSJ2, C9JNN9
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: November 30, 2010
    Last modified: October 1, 2014
    This is version 138 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    Target of thiazide diuretics used in the treatment of high blood pressure.1 Publication

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 16
      Human chromosome 16: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3