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P55017

- S12A3_HUMAN

UniProt

P55017 - S12A3_HUMAN

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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

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. sodium:chloride symporter activity Source: ProtInc
  2. 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
Complete GO annotation...

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
Complete GO annotation...

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

BgeeiP55017.
CleanExiHS_SLC12A3.
ExpressionAtlasiP55017. baseline and differential.
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.
GeneTreeiENSGT00760000119053.
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) [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

        10         20         30         40         50
MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST
60 70 80 90 100
FCMRTFGYNT IDVVPTYEHY ANSTQPGEPR KVRPTLADLH SFLKQEGRHL
110 120 130 140 150
HALAFDSRPS HEMTDGLVEG EAGTSSEKNP EEPVRFGWVK GVMIRCMLNI
160 170 180 190 200
WGVILYLRLP WITAQAGIVL TWIIILLSVT VTSITGLSIS AISTNGKVKS
210 220 230 240 250
GGTYFLISRS LGPELGGSIG LIFAFANAVG VAMHTVGFAE TVRDLLQEYG
260 270 280 290 300
APIVDPINDI RIIAVVSVTV LLAISLAGME WESKAQVLFF LVIMVSFANY
310 320 330 340 350
LVGTLIPPSE DKASKGFFSY RADIFVQNLV PDWRGPDGTF FGMFSIFFPS
360 370 380 390 400
ATGILAGANI SGDLKDPAIA IPKGTLMAIF WTTISYLAIS ATIGSCVVRD
410 420 430 440 450
ASGVLNDTVT PGWGACEGLA CSYGWNFTEC TQQHSCHYGL INYYQTMSMV
460 470 480 490 500
SGFAPLITAG IFGATLSSAL ACLVSAAKVF QCLCEDQLYP LIGFFGKGYG
510 520 530 540 550
KNKEPVRGYL LAYAIAVAFI IIAELNTIAP IISNFFLCSY ALINFSCFHA
560 570 580 590 600
SITNSPGWRP SFQYYNKWAA LFGAIISVVI MFLLTWWAAL IAIGVVLFLL
610 620 630 640 650
LYVIYKKPEV NWGSSVQAGS YNLALSYSVG LNEVEDHIKN YRPQCLVLTG
660 670 680 690 700
PPNFRPALVD FVGTFTRNLS LMICGHVLIG PHKQRMPELQ LIANGHTKWL
710 720 730 740 750
NKRKIKAFYS DVIAEDLRRG VQILMQAAGL GRMKPNILVV GFKKNWQSAH
760 770 780 790 800
PATVEDYIGI LHDAFDFNYG VCVMRMREGL NVSKMMQAHI NPVFDPAEDG
810 820 830 840 850
KEASARVDPK ALVKEEQATT IFQSEQGKKT IDIYWLFDDG GLTLLIPYLL
860 870 880 890 900
GRKRRWSKCK IRVFVGGQIN RMDQERKAII SLLSKFRLGF HEVHILPDIN
910 920 930 940 950
QNPRAEHTKR FEDMIAPFRL NDGFKDEATV NEMRRDCPWK ISDEEITKNR
960 970 980 990 1000
VKSLRQVRLN EIVLDYSRDA ALIVITLPIG RKGKCPSSLY MAWLETLSQD
1010 1020
LRPPVILIRG NQENVLTFYC Q
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.
GeneTreei ENSGT00760000119053.
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

Bgeei P55017.
CleanExi HS_SLC12A3.
ExpressionAtlasi P55017. baseline and differential.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 139 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