SLC12A3

Protein identityUniProt · HPA

UniProt accession

P55017

Gene

SLC12A3

Ensembl

ENSG00000070915

Chromosome

16

Canonical length

1021 aa

Protein class

Disease related genes, FDA approved drug targets, Human disease related genes, Metabolic proteins, Plasma proteins, Predicted membrane proteins, Transporters

Quaternary structure

Homodimer

OverviewNCBI Gene

This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Canonical amino-acid sequenceUniProt

1021 residues, UniProt reviewed canonical sequence.

>P55017|SLC12A3
     1  MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRTFGYNT
    61  IDVVPTYEHY ANSTQPGEPR KVRPTLADLH SFLKQEGRHL HALAFDSRPS HEMTDGLVEG
   121  EAGTSSEKNP EEPVRFGWVK GVMIRCMLNI WGVILYLRLP WITAQAGIVL TWIIILLSVT
   181  VTSITGLSIS AISTNGKVKS GGTYFLISRS LGPELGGSIG LIFAFANAVG VAMHTVGFAE
   241  TVRDLLQEYG APIVDPINDI RIIAVVSVTV LLAISLAGME WESKAQVLFF LVIMVSFANY
   301  LVGTLIPPSE DKASKGFFSY RADIFVQNLV PDWRGPDGTF FGMFSIFFPS ATGILAGANI
   361  SGDLKDPAIA IPKGTLMAIF WTTISYLAIS ATIGSCVVRD ASGVLNDTVT PGWGACEGLA
   421  CSYGWNFTEC TQQHSCHYGL INYYQTMSMV SGFAPLITAG IFGATLSSAL ACLVSAAKVF
   481  QCLCEDQLYP LIGFFGKGYG KNKEPVRGYL LAYAIAVAFI IIAELNTIAP IISNFFLCSY
   541  ALINFSCFHA SITNSPGWRP SFQYYNKWAA LFGAIISVVI MFLLTWWAAL IAIGVVLFLL
   601  LYVIYKKPEV NWGSSVQAGS YNLALSYSVG LNEVEDHIKN YRPQCLVLTG PPNFRPALVD
   661  FVGTFTRNLS LMICGHVLIG PHKQRMPELQ LIANGHTKWL NKRKIKAFYS DVIAEDLRRG
   721  VQILMQAAGL GRMKPNILVV GFKKNWQSAH PATVEDYIGI LHDAFDFNYG VCVMRMREGL
   781  NVSKMMQAHI NPVFDPAEDG KEASARVDPK ALVKEEQATT IFQSEQGKKT IDIYWLFDDG
   841  GLTLLIPYLL GRKRRWSKCK IRVFVGGQIN RMDQERKAII SLLSKFRLGF HEVHILPDIN
   901  QNPRAEHTKR FEDMIAPFRL NDGFKDEATV NEMRRDCPWK ISDEEITKNR VKSLRQVRLN
   961  EIVLDYSRDA ALIVITLPIG RKGKCPSSLY MAWLETLSQD LRPPVILIRG NQENVLTFYC
  1021  Q

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against SLC12A3 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Cell surface

Secreted

No

Transmembrane segments

9

Mean surface accessibility (rSASA)

0.29

Highest tissue expression

94 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about SLC12A3.

Disease | AllUniProt

Conditions SLC12A3 is implicated in, by any mechanism.

• Gitelman syndrome (GTLMNS) MIM:263800

Disease | GeneticClinVar

457 pathogenic / likely-pathogenic of 2,042 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Familial hypokalemia-hypomagnesemia
• Renal tubulopathies
• SLC12A3-related disorder
• Inborn genetic diseases
• Bartter syndrome

ReferencesPubMed · IEDB

Publications for SLC12A3 from three distinct lines of evidence, kept separate because they answer different questions: whether antibodies are directed at the protein, whether a B-cell epitope has been mapped on it, and whether a T-cell epitope has. Each is labelled with its source.

Sources: PubMed — antigen-level antibody evidence from a custom retrieval. Records matching a controlled set of autoantibody terms (the MeSH descriptors Autoantibodies and Autoantigens, with title and abstract term variants) were obtained through NCBI E-utilities, and their titles and abstracts parsed for constructions that direct an antibody at a named protein rather than for co-occurrence. Captured names were resolved against UniProt nomenclature and each antigen adjudicated individually against the source text. IEDB — curated epitope assays from the Immune Epitope Database (Vita et al., Nucleic Acids Research 2019). Bibliographic records from PubMed and MeSH, U.S. National Library of Medicine; citation metrics from NIH iCite (Hutchins et al., PLoS Biology 2016). Titles link to PubMed; abstracts are not reproduced here. The NLM does not endorse this analysis.

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

1.2

gnomAD pLI

0

gnomAD missense Z

-0.94

DepMap mean gene effect

-0.1

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 3% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• cell volume homeostasis
• chloride ion homeostasis
• chloride transmembrane transport
• monoatomic ion transport
• potassium ion homeostasis
• potassium ion import across plasma membrane
• renal sodium ion absorption
• response to aldosterone
• response to salt
• sodium ion homeostasis
• sodium ion transmembrane transport
• sodium ion transport

Molecular functions

• ATP binding
• sodium:chloride symporter activity
• sodium:potassium:chloride symporter activity

Cellular components

• apical plasma membrane
• cytosol
• extracellular exosome
• membrane
• plasma membrane

Protein domainsUniProt · Pfam · InterPro

• Amino acid permease/SLC12A domain
• SLC12A transporter family
• Amino acid permease, N-terminal
• SLC12A transporter, C-terminal
• Amino acid permease
• Solute carrier family 12
• Amino acid permease N-terminal
• Thiazide-sensitive Na-K-Cl co-transporter

KeywordsUniProt

• ATP-binding
• Cell membrane
• Chloride
• Disulfide bond
• Glycoprotein
• Ion transport
• Membrane
• Nucleotide-binding
• Phosphoprotein
• Sodium
• Sodium transport
• Symport
• Transmembrane
• Transmembrane helix
• Transport
• Ubl conjugation

InteractionsUniProt · HPA

Protein binding partners of SLC12A3 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• IL18R1
• KLHL3