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P55017 (S12A3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 133. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:SLC12A3
Synonyms:TSC
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1021 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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

Enzyme regulation

Activated by WNK3. Ref.5

Subunit structure

Interacts with KLHL3. Ref.7

Subcellular location

Cell membrane; Multi-pass membrane protein.

Tissue specificity

Predominant in kidney.

Post-translational modification

Ubiquitinated; ubiquitination is essential for regulation of endocytosis. The BCR(KLHL3) complex was initially identified as a candidate ubiquitin ligase for SLC12A3 (Ref.7). However, it was later shown that it is not the case. Ref.7

Involvement in disease

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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.6 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20

Miscellaneous

Target of thiazide diuretics used in the treatment of high blood pressure (Ref.1).

Sequence similarities

Belongs to the SLC12A transporter family.

Ontologies

Keywords
   Biological processIon transport
Sodium transport
Symport
Transport
   Cellular componentCell membrane
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainTransmembrane
Transmembrane helix
   LigandSodium
   PTMGlycoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processchloride transmembrane transport

Traceable author statement Ref.1. Source: GOC

chloride transport

Traceable author statement Ref.1. Source: GOC

ion transport

Traceable author statement. Source: Reactome

sodium ion transmembrane transport

Inferred from sequence or structural similarity. Source: BHF-UCL

sodium ion transport

Inferred from sequence or structural similarity. Source: UniProtKB

transmembrane transport

Traceable author statement. Source: Reactome

transport

Traceable author statement Ref.1PubMed 8670281. Source: ProtInc

   Cellular_componentapical plasma membrane

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Inferred from electronic annotation. Source: Ensembl

extracellular vesicular exosome

Inferred from direct assay PubMed 19056867. Source: UniProt

integral component of plasma membrane

Traceable author statement PubMed 8670281. Source: ProtInc

membrane

Traceable author statement PubMed 8670281. Source: ProtInc

plasma membrane

Traceable author statement. Source: Reactome

   Molecular_functionsodium:chloride symporter activity

Traceable author statement Ref.1. Source: ProtInc

transporter activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P55017-1)

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.
Isoform 2 (identifier: P55017-2)

The sequence of this isoform differs from the canonical sequence as follows:
     807-807: V → GARPSVSGAL
Isoform 3 (identifier: P55017-3)

The sequence of this isoform differs from the canonical sequence as follows:
     95-95: Missing.
     807-807: V → GARPSVSGAL
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 10211021Solute carrier family 12 member 3
PRO_0000178026

Regions

Topological domain1 – 135135Cytoplasmic Potential
Transmembrane136 – 15621Helical; Potential
Transmembrane159 – 17921Helical; Potential
Topological domain180 – 21839Cytoplasmic Potential
Transmembrane219 – 23921Helical; Potential
Transmembrane262 – 28221Helical; Potential
Topological domain283 – 2864Cytoplasmic Potential
Transmembrane287 – 30721Helical; Potential
Transmembrane340 – 36021Helical; Potential
Topological domain361 – 37717Cytoplasmic Potential
Transmembrane378 – 39821Helical; Potential
Transmembrane453 – 47321Helical; Potential
Topological domain474 – 51138Cytoplasmic Potential
Transmembrane512 – 53221Helical; Potential
Transmembrane535 – 55521Helical; Potential
Topological domain556 – 57722Cytoplasmic Potential
Transmembrane578 – 59821Helical; Potential
Transmembrane661 – 68121Helical; Potential
Topological domain682 – 1021340Cytoplasmic Potential

Amino acid modifications

Glycosylation4061N-linked (GlcNAc...) Potential
Glycosylation4261N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence951Missing in isoform 3.
VSP_040100
Alternative sequence8071V → GARPSVSGAL in isoform 2 and isoform 3.
VSP_036318
Natural variant601T → M in GS. Ref.16
VAR_039475
Natural variant621D → N in GS. Ref.6
VAR_039476
Natural variant681E → K in GS. Ref.19
VAR_039477
Natural variant691H → N in GS. Ref.19
VAR_039478
Natural variant901H → Y in GS. Ref.17
VAR_039479
Natural variant1451R → H in GS. Ref.19
VAR_039480
Natural variant1531V → M in GS. Ref.19
VAR_039481
Natural variant1541I → F in GS. Ref.12
VAR_039482
Natural variant1581R → Q in GS. Ref.15
VAR_039483
Natural variant1631T → M in GS. Ref.15
VAR_039484
Natural variant1721W → R in GS. Ref.15
VAR_039485
Natural variant1781S → L in GS. Ref.12
VAR_039486
Natural variant1801T → K in GS. Ref.11
Corresponds to variant rs146158333 [ dbSNP | Ensembl ].
VAR_039487
Natural variant1861G → D in GS. Ref.6
VAR_039488
Natural variant2091R → Q in GS. Ref.12
Corresponds to variant rs28936388 [ dbSNP | Ensembl ].
VAR_039489
Natural variant2091R → W in GS. Ref.1 Ref.6 Ref.9 Ref.15
Corresponds to variant rs28936388 [ dbSNP | Ensembl ].
VAR_007113
Natural variant2151L → P in GS. Ref.9
VAR_039490
Natural variant2261A → T in GS. Ref.9
VAR_039491
Natural variant2301G → D in GS. Ref.19
VAR_039492
Natural variant2611R → H in GS. Ref.9
VAR_039493
Natural variant2641A → G. Ref.1 Ref.2 Ref.3 Ref.13 Ref.21
Corresponds to variant rs1529927 [ dbSNP | Ensembl ].
VAR_039494
Natural variant2831S → Y in GS. Ref.17
VAR_039495
Natural variant2841K → R in GS. Ref.12
VAR_039496
Natural variant3041T → P in GS. Ref.10
VAR_039497
Natural variant3131A → V in GS. Ref.12
VAR_039498
Natural variant3161G → V in GS. Ref.15
VAR_039499
Natural variant3211R → W in GS. Ref.12
VAR_039500
Natural variant3341R → W in GS. Ref.12
VAR_039501
Natural variant3421G → A in GS. Ref.19
VAR_039502
Natural variant3491P → L in GS. Ref.1 Ref.6
VAR_007114
Natural variant3741G → V in GS. Ref.15
VAR_039503
Natural variant3991R → C in GS. Ref.12
VAR_039504
Natural variant4211C → R in GS. Ref.1
Corresponds to variant rs28936387 [ dbSNP | Ensembl ].
VAR_007115
Natural variant4391G → S in GS. Ref.6 Ref.10
VAR_039505
Natural variant4631G → E in GS. Ref.15
VAR_039506
Natural variant4641A → T in GS. Ref.15
VAR_039507
Natural variant4781K → E in GS. Ref.6
VAR_039508
Natural variant4861D → N in GS. Ref.1 Ref.6
VAR_007116
Natural variant4961G → C in GS. Ref.1 Ref.6
VAR_007117
Natural variant5421L → P in GS. Ref.6
VAR_039509
Natural variant5551S → L in GS. Ref.12
VAR_039510
Natural variant5601P → H in GS. Ref.9
VAR_039511
Natural variant5611Missing in GS. Ref.1
VAR_007118
Natural variant5691A → E in GS. Ref.11
VAR_039512
Natural variant5691A → V in GS. Ref.16
VAR_039513
Natural variant5781V → M in GS. Ref.11
Corresponds to variant rs139329616 [ dbSNP | Ensembl ].
VAR_039514
Natural variant5881A → V in GS. Ref.1 Ref.6
VAR_007119
Natural variant6131G → S in GS. Ref.9
VAR_039515
Natural variant6151S → L in GS. Ref.12 Ref.15
VAR_039516
Natural variant6151S → W in GS. Ref.15
VAR_039517
Natural variant6231L → P in GS. Ref.8 Ref.14
VAR_039518
Natural variant6301G → V in GS. Ref.1
Corresponds to variant rs28936389 [ dbSNP | Ensembl ].
VAR_007120
Natural variant6421R → C in GS. Ref.11 Ref.16
Corresponds to variant rs200697179 [ dbSNP | Ensembl ].
VAR_039519
Natural variant6421R → G in GS. Ref.12 Ref.15
VAR_039520
Natural variant6421R → H in GS. Ref.9 Ref.15
VAR_039521
Natural variant6431P → L in GS. Ref.12 Ref.13
Corresponds to variant rs140012781 [ dbSNP | Ensembl ].
VAR_039522
Natural variant6491T → R in GS. Ref.9
VAR_039523
Natural variant6551R → C in GS. Ref.9
VAR_039524
Natural variant6551R → H in GS. Ref.1
VAR_007121
Natural variant6551R → L in GS. Ref.1
VAR_007122
Natural variant6721M → I in GS. Ref.18
VAR_039525
Natural variant6771V → L in GS. Ref.19
VAR_039526
Natural variant6771V → M in GS. Ref.15
VAR_039527
Natural variant7281A → T. Ref.1 Ref.21
Corresponds to variant rs36049418 [ dbSNP | Ensembl ].
VAR_007123
Natural variant7291G → V in GS. Ref.12
VAR_039528
Natural variant7311G → R in GS. Ref.6 Ref.10
VAR_039529
Natural variant7381L → R in GS. Ref.9
VAR_039530
Natural variant7411G → R in GS. Ref.1 Ref.9 Ref.10
Corresponds to variant rs138977195 [ dbSNP | Ensembl ].
VAR_007124
Natural variant8491L → H in GS. Ref.11 Ref.16 Ref.20
Corresponds to variant rs185927948 [ dbSNP | Ensembl ].
VAR_039531
Natural variant8501L → P in GS. Ref.1 Ref.9
VAR_007125
Natural variant8521R → C in GS. Ref.9 Ref.15
VAR_039532
Natural variant8521R → H in GS. Ref.20
VAR_039533
Natural variant8521R → S in GS. Ref.15
VAR_039534
Natural variant8541R → K.
Corresponds to variant rs8060046 [ dbSNP | Ensembl ].
VAR_060106
Natural variant8671G → S in GS. Ref.19
VAR_039535
Natural variant8711R → H in GS. Ref.17
VAR_039536
Natural variant9041R → Q. Ref.9 Ref.10 Ref.15 Ref.21
Corresponds to variant rs11643718 [ dbSNP | Ensembl ].
VAR_039537
Natural variant9191R → C Increases sodium transport. Ref.9 Ref.21
Corresponds to variant rs12708965 [ dbSNP | Ensembl ].
VAR_039538
Natural variant9551R → Q in GS. Ref.1
VAR_007126
Natural variant9581R → G in GS. Ref.15
VAR_039539
Natural variant9851C → Y in GS. Ref.15
Corresponds to variant rs199849117 [ dbSNP | Ensembl ].
VAR_039540

Experimental info

Sequence conflict459 – 4602AG → VV in CAA62613. Ref.2
Sequence conflict5391S → P in AK315298. Ref.3
Sequence conflict7661D → E in AAC50355. Ref.1
Sequence conflict7781Missing in AK315298. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 30, 2010. Version 3.
Checksum: 629C5A42F3234B71

FASTA1,021113,139
        10         20         30         40         50         60 
MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRTFGYNT 

        70         80         90        100        110        120 
IDVVPTYEHY ANSTQPGEPR KVRPTLADLH SFLKQEGRHL HALAFDSRPS HEMTDGLVEG 

       130        140        150        160        170        180 
EAGTSSEKNP EEPVRFGWVK GVMIRCMLNI WGVILYLRLP WITAQAGIVL TWIIILLSVT 

       190        200        210        220        230        240 
VTSITGLSIS AISTNGKVKS GGTYFLISRS LGPELGGSIG LIFAFANAVG VAMHTVGFAE 

       250        260        270        280        290        300 
TVRDLLQEYG APIVDPINDI RIIAVVSVTV LLAISLAGME WESKAQVLFF LVIMVSFANY 

       310        320        330        340        350        360 
LVGTLIPPSE DKASKGFFSY RADIFVQNLV PDWRGPDGTF FGMFSIFFPS ATGILAGANI 

       370        380        390        400        410        420 
SGDLKDPAIA IPKGTLMAIF WTTISYLAIS ATIGSCVVRD ASGVLNDTVT PGWGACEGLA 

       430        440        450        460        470        480 
CSYGWNFTEC TQQHSCHYGL INYYQTMSMV SGFAPLITAG IFGATLSSAL ACLVSAAKVF 

       490        500        510        520        530        540 
QCLCEDQLYP LIGFFGKGYG KNKEPVRGYL LAYAIAVAFI IIAELNTIAP IISNFFLCSY 

       550        560        570        580        590        600 
ALINFSCFHA SITNSPGWRP SFQYYNKWAA LFGAIISVVI MFLLTWWAAL IAIGVVLFLL 

       610        620        630        640        650        660 
LYVIYKKPEV NWGSSVQAGS YNLALSYSVG LNEVEDHIKN YRPQCLVLTG PPNFRPALVD 

       670        680        690        700        710        720 
FVGTFTRNLS LMICGHVLIG PHKQRMPELQ LIANGHTKWL NKRKIKAFYS DVIAEDLRRG 

       730        740        750        760        770        780 
VQILMQAAGL GRMKPNILVV GFKKNWQSAH PATVEDYIGI LHDAFDFNYG VCVMRMREGL 

       790        800        810        820        830        840 
NVSKMMQAHI NPVFDPAEDG KEASARVDPK ALVKEEQATT IFQSEQGKKT IDIYWLFDDG 

       850        860        870        880        890        900 
GLTLLIPYLL GRKRRWSKCK IRVFVGGQIN RMDQERKAII SLLSKFRLGF HEVHILPDIN 

       910        920        930        940        950        960 
QNPRAEHTKR FEDMIAPFRL NDGFKDEATV NEMRRDCPWK ISDEEITKNR VKSLRQVRLN 

       970        980        990       1000       1010       1020 
EIVLDYSRDA ALIVITLPIG RKGKCPSSLY MAWLETLSQD LRPPVILIRG NQENVLTFYC 


Q 

« Hide

Isoform 2 [UniParc].

Checksum: 5CB36A5FF81494A3
Show »

FASTA1,030113,936
Isoform 3 [UniParc].

Checksum: DD190B2391AE0525
Show »

FASTA1,029113,808

References

« Hide 'large scale' references
[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. expand/collapse author list , 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. expand/collapse author list , 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]"Similar Effects of all WNK3 Variants upon SLC12 Cotransporters."
Cruz-Rangel S., Melo Z., Vazquez N., Meade P., Bobadilla N.A., Pasantes-Morales H., Gamba G., Mercado A.
Am. J. Physiol. 301:C601-C608(2011) [PubMed] [Europe PMC] [Abstract]
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]"KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron."
Louis-Dit-Picard H., Barc J., Trujillano D., Miserey-Lenkei S., Bouatia-Naji N., Pylypenko O., Beaurain G., Bonnefond A., Sand O., Simian C., Vidal-Petiot E., Soukaseum C., Mandet C., Broux F., Chabre O., Delahousse M., Esnault V., Fiquet B. expand/collapse author list , Houillier P., Bagnis C.I., Koenig J., Konrad M., Landais P., Mourani C., Niaudet P., Probst V., Thauvin C., Unwin R.J., Soroka S.D., Ehret G., Ossowski S., Caulfield M., Bruneval P., Estivill X., Froguel P., Hadchouel J., Schott J.J., Jeunemaitre X.
Nat. Genet. 44:456-460(2012) [PubMed] [Europe PMC] [Abstract]
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]"Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes."
Fava C., Montagnana M., Rosberg L., Burri P., Joensson A., Wanby P., Wahrenberg H., Hulthen U.L., Aurell M., Guidi G.C., Melander O.
DNA Seq. 18:395-399(2007) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U44128 mRNA. Translation: AAC50355.1.
X91220 mRNA. Translation: CAA62613.1.
AK315298 mRNA. No translation available.
AC012181 Genomic DNA. No translation available.
PIRG01202.
PC4180.
RefSeqNP_000330.2. NM_000339.2.
NP_001119579.1. NM_001126107.1.
NP_001119580.1. NM_001126108.1.
UniGeneHs.669115.

3D structure databases

ProteinModelPortalP55017.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112448. 11 interactions.
STRING9606.ENSP00000262502.

Chemistry

ChEMBLCHEMBL1876.
DrugBankDB00436. Bendroflumethiazide.
DB00562. Benzthiazide.
DB00880. Chlorothiazide.
DB01119. Diazoxide.
DB00999. Hydrochlorothiazide.
DB00524. Metolazone.
DB01324. Polythiazide.
DB01325. Quinethazone.
GuidetoPHARMACOLOGY970.

Protein family/group databases

TCDB2.A.30.4.2. the cation-chloride cotransporter (ccc) family.

PTM databases

PhosphoSiteP55017.

Polymorphism databases

DMDM313104194.

Proteomic databases

PaxDbP55017.
PRIDEP55017.

Protocols and materials databases

DNASU6559.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000438926; ENSP00000402152; ENSG00000070915. [P55017-2]
ENST00000563236; ENSP00000456149; ENSG00000070915. [P55017-1]
ENST00000566786; ENSP00000457552; ENSG00000070915. [P55017-3]
GeneID6559.
KEGGhsa:6559.
UCSCuc002ekd.4. human. [P55017-2]
uc010ccm.3. human. [P55017-1]
uc010ccn.3. human. [P55017-3]

Organism-specific databases

CTD6559.
GeneCardsGC16P056899.
HGNCHGNC:10912. SLC12A3.
HPACAB022505.
HPA028748.
MIM263800. phenotype.
600968. gene.
neXtProtNX_P55017.
Orphanet358. Gitelman syndrome.
PharmGKBPA321.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0531.
HOGENOMHOG000062855.
HOVERGENHBG052851.
InParanoidP55017.
KOK14426.
OMAQLYPLIG.
OrthoDBEOG75MVVC.
PhylomeDBP55017.
TreeFamTF313191.

Enzyme and pathway databases

ReactomeREACT_15518. Transmembrane transport of small molecules.

Gene expression databases

ArrayExpressP55017.
BgeeP55017.
CleanExHS_SLC12A3.
GenevestigatorP55017.

Family and domain databases

InterProIPR004841. AA-permease/SLC12A_dom.
IPR013612. AA_permease_N.
IPR004842. Na/K/Cl_cotransptS.
IPR002948. NaCl_cotranspt.
[Graphical view]
PfamPF00324. AA_permease. 1 hit.
PF08403. AA_permease_N. 1 hit.
[Graphical view]
PRINTSPR01230. NACLTRNSPORT.
TIGRFAMsTIGR00930. 2a30. 1 hit.
ProtoNetSearch...

Other

GeneWikiSodium-chloride_symporter.
GenomeRNAi6559.
NextBio25523.
PROP55017.
SOURCESearch...

Entry information

Entry nameS12A3_HUMAN
AccessionPrimary (citable) accession number: P55017
Secondary accession number(s): A8MSJ2, C9JNN9
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: November 30, 2010
Last modified: April 16, 2014
This is version 133 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 16

Human chromosome 16: entries, gene names and cross-references to MIM