P55017 (S12A3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	SLC12A3
Synonyms:	TSC

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1021 AA.
Sequence status	Complete.
Protein existence	Evidence 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 By similarity. May be ubiquitinated by the BCR(KLHL3) complex. 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 process	Ion transport Sodium transport Symport Transport
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Transmembrane Transmembrane helix
Ligand	Sodium
PTM	Glycoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	sodium ion transmembrane transport Inferred from sequence or structural similarity. Source: BHF-UCL
Cellular_component	apical plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB cytosol Inferred from electronic annotation. Source: Compara integral to plasma membrane Traceable author statement PubMed 8670281. Source: ProtInc
Molecular_function	sodium:chloride symporter activity Traceable author statement Ref.1. Source: ProtInc
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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1021	1021	Solute carrier family 12 member 3		PRO_0000178026
Regions
	Topological domain	1 – 135	135	Cytoplasmic Potential
	Transmembrane	136 – 156	21	Helical; Potential
	Transmembrane	159 – 179	21	Helical; Potential
	Topological domain	180 – 218	39	Cytoplasmic Potential
	Transmembrane	219 – 239	21	Helical; Potential
	Transmembrane	262 – 282	21	Helical; Potential
	Topological domain	283 – 286	4	Cytoplasmic Potential
	Transmembrane	287 – 307	21	Helical; Potential
	Transmembrane	340 – 360	21	Helical; Potential
	Topological domain	361 – 377	17	Cytoplasmic Potential
	Transmembrane	378 – 398	21	Helical; Potential
	Transmembrane	453 – 473	21	Helical; Potential
	Topological domain	474 – 511	38	Cytoplasmic Potential
	Transmembrane	512 – 532	21	Helical; Potential
	Transmembrane	535 – 555	21	Helical; Potential
	Topological domain	556 – 577	22	Cytoplasmic Potential
	Transmembrane	578 – 598	21	Helical; Potential
	Transmembrane	661 – 681	21	Helical; Potential
	Topological domain	682 – 1021	340	Cytoplasmic Potential
Amino acid modifications
	Glycosylation	406	1	N-linked (GlcNAc...) Potential
	Glycosylation	426	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	95	1	Missing in isoform 3.		VSP_040100
	Alternative sequence	807	1	V → GARPSVSGAL in isoform 2 and isoform 3.		VSP_036318
	Natural variant	60	1	T → M in GS. Ref.16		VAR_039475
	Natural variant	62	1	D → N in GS. Ref.6		VAR_039476
	Natural variant	68	1	E → K in GS. Ref.19		VAR_039477
	Natural variant	69	1	H → N in GS. Ref.19		VAR_039478
	Natural variant	90	1	H → Y in GS. Ref.17		VAR_039479
	Natural variant	145	1	R → H in GS. Ref.19		VAR_039480
	Natural variant	153	1	V → M in GS. Ref.19		VAR_039481
	Natural variant	154	1	I → F in GS. Ref.12		VAR_039482
	Natural variant	158	1	R → Q in GS. Ref.15		VAR_039483
	Natural variant	163	1	T → M in GS. Ref.15		VAR_039484
	Natural variant	172	1	W → R in GS. Ref.15		VAR_039485
	Natural variant	178	1	S → L in GS. Ref.12		VAR_039486
	Natural variant	180	1	T → K in GS. Ref.11		VAR_039487
	Natural variant	186	1	G → D in GS. Ref.6		VAR_039488
	Natural variant	209	1	R → Q in GS. Ref.12 Corresponds to variant rs28936388 [ dbSNP | Ensembl ].		VAR_039489
	Natural variant	209	1	R → W in GS. Ref.1 Ref.6 Ref.9 Ref.15 Corresponds to variant rs28936388 [ dbSNP | Ensembl ].		VAR_007113
	Natural variant	215	1	L → P in GS. Ref.9		VAR_039490
	Natural variant	226	1	A → T in GS. Ref.9		VAR_039491
	Natural variant	230	1	G → D in GS. Ref.19		VAR_039492
	Natural variant	261	1	R → H in GS. Ref.9		VAR_039493
	Natural variant	264	1	A → G. Ref.1 Ref.2 Ref.3 Ref.13 Ref.21 Corresponds to variant rs1529927 [ dbSNP | Ensembl ].		VAR_039494
	Natural variant	283	1	S → Y in GS. Ref.17		VAR_039495
	Natural variant	284	1	K → R in GS. Ref.12		VAR_039496
	Natural variant	304	1	T → P in GS. Ref.10		VAR_039497
	Natural variant	313	1	A → V in GS. Ref.12		VAR_039498
	Natural variant	316	1	G → V in GS. Ref.15		VAR_039499
	Natural variant	321	1	R → W in GS. Ref.12		VAR_039500
	Natural variant	334	1	R → W in GS. Ref.12		VAR_039501
	Natural variant	342	1	G → A in GS. Ref.19		VAR_039502
	Natural variant	349	1	P → L in GS. Ref.1 Ref.6		VAR_007114
	Natural variant	374	1	G → V in GS. Ref.15		VAR_039503
	Natural variant	399	1	R → C in GS. Ref.12		VAR_039504
	Natural variant	421	1	C → R in GS. Ref.1 Corresponds to variant rs28936387 [ dbSNP | Ensembl ].		VAR_007115
	Natural variant	439	1	G → S in GS. Ref.6 Ref.10		VAR_039505
	Natural variant	463	1	G → E in GS. Ref.15		VAR_039506
	Natural variant	464	1	A → T in GS. Ref.15		VAR_039507
	Natural variant	478	1	K → E in GS. Ref.6		VAR_039508
	Natural variant	486	1	D → N in GS. Ref.1 Ref.6		VAR_007116
	Natural variant	496	1	G → C in GS. Ref.1 Ref.6		VAR_007117
	Natural variant	542	1	L → P in GS. Ref.6		VAR_039509
	Natural variant	555	1	S → L in GS. Ref.12		VAR_039510
	Natural variant	560	1	P → H in GS. Ref.9		VAR_039511
	Natural variant	561	1	Missing in GS. Ref.1		VAR_007118
	Natural variant	569	1	A → E in GS. Ref.11		VAR_039512
	Natural variant	569	1	A → V in GS. Ref.16		VAR_039513
	Natural variant	578	1	V → M in GS. Ref.11		VAR_039514
	Natural variant	588	1	A → V in GS. Ref.1 Ref.6		VAR_007119
	Natural variant	613	1	G → S in GS. Ref.9		VAR_039515
	Natural variant	615	1	S → L in GS. Ref.12 Ref.15		VAR_039516
	Natural variant	615	1	S → W in GS. Ref.15		VAR_039517
	Natural variant	623	1	L → P in GS. Ref.8 Ref.14		VAR_039518
	Natural variant	630	1	G → V in GS. Ref.1 Corresponds to variant rs28936389 [ dbSNP | Ensembl ].		VAR_007120
	Natural variant	642	1	R → C in GS. Ref.11 Ref.16		VAR_039519
	Natural variant	642	1	R → G in GS. Ref.12 Ref.15		VAR_039520
	Natural variant	642	1	R → H in GS. Ref.9 Ref.15		VAR_039521
	Natural variant	643	1	P → L in GS. Ref.12 Ref.13		VAR_039522
	Natural variant	649	1	T → R in GS. Ref.9		VAR_039523
	Natural variant	655	1	R → C in GS. Ref.9		VAR_039524
	Natural variant	655	1	R → H in GS. Ref.1		VAR_007121
	Natural variant	655	1	R → L in GS. Ref.1		VAR_007122
	Natural variant	672	1	M → I in GS. Ref.18		VAR_039525
	Natural variant	677	1	V → L in GS. Ref.19		VAR_039526
	Natural variant	677	1	V → M in GS. Ref.15		VAR_039527
	Natural variant	728	1	A → T. Ref.1 Ref.21 Corresponds to variant rs36049418 [ dbSNP | Ensembl ].		VAR_007123
	Natural variant	729	1	G → V in GS. Ref.12		VAR_039528
	Natural variant	731	1	G → R in GS. Ref.6 Ref.10		VAR_039529
	Natural variant	738	1	L → R in GS. Ref.9		VAR_039530
	Natural variant	741	1	G → R in GS. Ref.1 Ref.9 Ref.10		VAR_007124
	Natural variant	849	1	L → H in GS. Ref.11 Ref.16 Ref.20		VAR_039531
	Natural variant	850	1	L → P in GS. Ref.1 Ref.9		VAR_007125
	Natural variant	852	1	R → C in GS. Ref.9 Ref.15		VAR_039532
	Natural variant	852	1	R → H in GS. Ref.20		VAR_039533
	Natural variant	852	1	R → S in GS. Ref.15		VAR_039534
	Natural variant	854	1	R → K. Corresponds to variant rs8060046 [ dbSNP | Ensembl ].		VAR_060106
	Natural variant	867	1	G → S in GS. Ref.19		VAR_039535
	Natural variant	871	1	R → H in GS. Ref.17		VAR_039536
	Natural variant	904	1	R → Q. Ref.9 Ref.10 Ref.15 Ref.21 Corresponds to variant rs11643718 [ dbSNP | Ensembl ].		VAR_039537
	Natural variant	919	1	R → C Increases sodium transport. Ref.9 Ref.21 Corresponds to variant rs12708965 [ dbSNP | Ensembl ].		VAR_039538
	Natural variant	955	1	R → Q in GS. Ref.1		VAR_007126
	Natural variant	958	1	R → G in GS. Ref.15		VAR_039539
	Natural variant	985	1	C → Y in GS. Ref.15		VAR_039540
Experimental info
	Sequence conflict	459 – 460	2	AG → VV in CAA62613. Ref.2
	Sequence conflict	539	1	S → P in AK315298. Ref.3
	Sequence conflict	766	1	D → E in AAC50355. Ref.1
	Sequence conflict	778	1	Missing in AK315298. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 30, 2010. Version 3. Checksum: 629C5A42F3234B71	FASTA	1,021	113,139
	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
	Isoform 2 [UniParc]. Checksum: 5CB36A5FF81494A3	FASTA	1,030	113,936
	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 KEASARGARP SVSGALDPKA LVKEEQATTI FQSEQGKKTI 850 860 870 880 890 900 DIYWLFDDGG LTLLIPYLLG RKRRWSKCKI RVFVGGQINR MDQERKAIIS LLSKFRLGFH 910 920 930 940 950 960 EVHILPDINQ NPRAEHTKRF EDMIAPFRLN DGFKDEATVN EMRRDCPWKI SDEEITKNRV 970 980 990 1000 1010 1020 KSLRQVRLNE IVLDYSRDAA LIVITLPIGR KGKCPSSLYM AWLETLSQDL RPPVILIRGN 1030 QENVLTFYCQ
	Isoform 3 [UniParc]. Checksum: DD190B2391AE0525	FASTA	1,029	113,808
	10 20 30 40 50 60 MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRTFGYNT 70 80 90 100 110 120 IDVVPTYEHY ANSTQPGEPR KVRPTLADLH SFLKEGRHLH ALAFDSRPSH EMTDGLVEGE 130 140 150 160 170 180 AGTSSEKNPE EPVRFGWVKG VMIRCMLNIW GVILYLRLPW ITAQAGIVLT WIIILLSVTV 190 200 210 220 230 240 TSITGLSISA ISTNGKVKSG GTYFLISRSL GPELGGSIGL IFAFANAVGV AMHTVGFAET 250 260 270 280 290 300 VRDLLQEYGA PIVDPINDIR IIAVVSVTVL LAISLAGMEW ESKAQVLFFL VIMVSFANYL 310 320 330 340 350 360 VGTLIPPSED KASKGFFSYR ADIFVQNLVP DWRGPDGTFF GMFSIFFPSA TGILAGANIS 370 380 390 400 410 420 GDLKDPAIAI PKGTLMAIFW TTISYLAISA TIGSCVVRDA SGVLNDTVTP GWGACEGLAC 430 440 450 460 470 480 SYGWNFTECT QQHSCHYGLI NYYQTMSMVS GFAPLITAGI FGATLSSALA CLVSAAKVFQ 490 500 510 520 530 540 CLCEDQLYPL IGFFGKGYGK NKEPVRGYLL AYAIAVAFII IAELNTIAPI ISNFFLCSYA 550 560 570 580 590 600 LINFSCFHAS ITNSPGWRPS FQYYNKWAAL FGAIISVVIM FLLTWWAALI AIGVVLFLLL 610 620 630 640 650 660 YVIYKKPEVN WGSSVQAGSY NLALSYSVGL NEVEDHIKNY RPQCLVLTGP PNFRPALVDF 670 680 690 700 710 720 VGTFTRNLSL MICGHVLIGP HKQRMPELQL IANGHTKWLN KRKIKAFYSD VIAEDLRRGV 730 740 750 760 770 780 QILMQAAGLG RMKPNILVVG FKKNWQSAHP ATVEDYIGIL HDAFDFNYGV CVMRMREGLN 790 800 810 820 830 840 VSKMMQAHIN PVFDPAEDGK EASARGARPS VSGALDPKAL VKEEQATTIF QSEQGKKTID 850 860 870 880 890 900 IYWLFDDGGL TLLIPYLLGR KRRWSKCKIR VFVGGQINRM DQERKAIISL LSKFRLGFHE 910 920 930 940 950 960 VHILPDINQN PRAEHTKRFE DMIAPFRLND GFKDEATVNE MRRDCPWKIS DEEITKNRVK 970 980 990 1000 1010 1020 SLRQVRLNEI VLDYSRDAAL IVITLPIGRK GKCPSSLYMA WLETLSQDLR PPVILIRGNQ ENVLTFYCQ

References

	« Hide 'large scale' referencesShow '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. , 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]	"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. , 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. 0:0-0(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

GeneReviews

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.
IPI	IPI00216438. IPI00646907. IPI00893513.
PIR	G01202. PC4180.
RefSeq	NP_000330.2. NM_000339.2. NP_001119579.1. NM_001126107.1. NP_001119580.1. NM_001126108.1.
UniGene	Hs.669115.
3D structure databases
ProteinModelPortal	P55017.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000262502.
Protein family/group databases
TCDB	2.A.30.4.2. cation-chloride cotransporter (CCC) family.
PTM databases
PhosphoSite	P55017.
Proteomic databases
PaxDb	P55017.
PRIDE	P55017.
Protocols and materials databases
DNASU	6559.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000438926; ENSP00000402152; ENSG00000070915. ENST00000563236; ENSP00000456149; ENSG00000070915. ENST00000566786; ENSP00000457552; ENSG00000070915.
GeneID	6559.
KEGG	hsa:6559.
UCSC	uc002ekd.4. human. uc010ccm.3. human. uc010ccn.3. human.
Organism-specific databases
CTD	6559.
GeneCards	GC16P056899.
HGNC	HGNC:10912. SLC12A3.
HPA	CAB022505. HPA028748.
MIM	263800. phenotype. 600968. gene.
neXtProt	NX_P55017.
Orphanet	358. Gitelman syndrome.
PharmGKB	PA321.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0531.
HOGENOM	HOG000062855.
HOVERGEN	HBG052851.
InParanoid	P55017.
KO	K14426.
OMA	IGRKGKC.
OrthoDB	EOG4CC40K.
Enzyme and pathway databases
Reactome	REACT_15518. Transmembrane transport of small molecules.
Gene expression databases
Bgee	P55017.
CleanEx	HS_SLC12A3.
Genevestigator	P55017.
GermOnline	ENSG00000070915. Homo sapiens.
Family and domain databases
InterPro	IPR004841. AA-permease_dom. IPR013612. AA_permease_N. IPR004842. Na/K/Cl_cotransptS. IPR002948. NaCl_cotranspt. [Graphical view]
Pfam	PF00324. AA_permease. 1 hit. PF08403. AA_permease_N. 1 hit. [Graphical view]
PRINTS	PR01230. NACLTRNSPORT.
TIGRFAMs	TIGR00930. 2a30. 1 hit.
ProtoNet	Search...
Other
ChEMBL	CHEMBL1876.
DrugBank	DB00436. Bendroflumethiazide. DB00562. Benzthiazide. DB00880. Chlorothiazide. DB01119. Diazoxide. DB00999. Hydrochlorothiazide. DB00524. Metolazone. DB01324. Polythiazide. DB01325. Quinethazone.
GenomeRNAi	6559.
NextBio	25523.
SOURCE	Search...

Entry information

Entry name

S12A3_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 123 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.