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SLC12A4 solute carrier family 12 member 4 [ Homo sapiens (human) ]

Gene ID: 6560, updated on 3-Nov-2024

Summary

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Official Symbol
SLC12A4provided by HGNC
Official Full Name
solute carrier family 12 member 4provided by HGNC
Primary source
HGNC:HGNC:10913
See related
Ensembl:ENSG00000124067 MIM:604119; AllianceGenome:HGNC:10913
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
KCC1; hKCC1; CTC-479C5.17
Summary
This gene encodes a member of the SLC12A transporter family. The encoded protein mediates the coupled movement of potassium and chloride ions across the plasma membrane. This gene is expressed ubiquitously. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2013]
Expression
Ubiquitous expression in lung (RPKM 18.3), placenta (RPKM 18.1) and 25 other tissues See more
Orthologs
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Genomic context

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See SLC12A4 in Genome Data Viewer
Location:
16q22.1
Exon count:
26
Annotation release Status Assembly Chr Location
RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 16 NC_000016.10 (67943474..67968694, complement)
RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 16 NC_060940.1 (73739247..73764467, complement)
RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 16 NC_000016.9 (67977377..68002597, complement)

Chromosome 16 - NC_000016.10Genomic Context describing neighboring genes Neighboring gene protein serine kinase H1 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:67964222-67964739 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:67964740-67965256 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10993 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10994 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10995 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10996 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:67973687-67974296 Neighboring gene chymotrypsin like Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10998 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:67976255-67977154 Neighboring gene proteasome 20S subunit beta 10 Neighboring gene lecithin-cholesterol acyltransferase Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr16:67992978-67994177 Neighboring gene ReSE screen-validated silencer GRCh37_chr16:67998939-67999110 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68000156-68000674 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7633 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7634 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7635 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:68013726-68014226 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7636 Neighboring gene Sharpr-MPRA regulatory region 6452 Neighboring gene dipeptidase 3 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10999 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11000 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11001 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7637 Neighboring gene dipeptidase 2 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:68031810-68032326

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. Molecular operation of the cation chloride cotransporters: ion binding and inhibitor interaction. Payne JA. Curr Top Membr, 2012. PMID 23177987
  2. K(+)-Cl(-) cotransporter 1 (KCC1): a housekeeping membrane protein that plays key supplemental roles in hematopoietic and cancer cells. Garneau AP, et al. J Hematol Oncol, 2019 Jul 11. PMID 31296230, Free PMC Article
  3. The role of potassium chloride cotransporters in murine and human sperm volume regulation. Klein T, et al. Biol Reprod, 2006 Dec. PMID 16943364
  4. Oxygen dependence of K(+)-Cl- cotransport in human red cell ghosts and sickle cells. Khan AI, et al. Bioelectrochemistry, 2004 May. PMID 15039017
  5. Human potassium chloride cotransporter 1 (SLC12A4) promoter is regulated by AP-2 and contains a functional downstream promoter element. Zhou GP, et al. Blood, 2004 Jun 1. PMID 14976052

See all (72) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Structure of the human cation-chloride cotransport KCC1 in an outward-open state.
    Title: Structure of the human cation-chloride cotransport KCC1 in an outward-open state.
  2. The main goal of the review is to discuss the molecular features and tissue-specific functions of KCC1 from the hematological perspective for the greater part. As will be seen, the characterization of KCC1 has led the way to important findings and promising therapeutic avenues. [review]
    Title: K(+)-Cl(-) cotransporter 1 (KCC1): a housekeeping membrane protein that plays key supplemental roles in hematopoietic and cancer cells.
  3. data indicate that Zn(2+) acting via ZnR/GPR39 has a direct role in controlling Cl(-) absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets.
    Title: The Zn(2+)-sensing receptor, ZnR/GPR39, upregulates colonocytic Cl(-) absorption, via basolateral KCC1, and reduces fluid loss.
  4. The Wnk3 protein isoforms have a similar effect on SLC12 cotransporters. NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions.
    Title: Similar effects of all WNK3 variants on SLC12 cotransporters.
  5. Insulin-like growth factors I can induce the upregulation of KCC1 gene, and KCC1 gene participates in the invasion ability of HEC-1B cells through the ERK signaling pathway.
    Title: KCC1 gene advances cell invasion ability by regulating ERK signaling pathway in endometrial cancer HEC-1B cell line.
  6. KCC3 is the dominant isoform in erythrocytes, with variable expression of KCC1 and KCC4 that could result in modulation of KCC activity
    Title: K-Cl cotransporter gene expression during human and murine erythroid differentiation.
  7. Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
    Title: Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
  8. Observational study of gene-disease association. (HuGE Navigator)
    Title: Physiogenomic analysis of statin-treated patients: domain-specific counter effects within the ACACB gene on low-density lipoprotein cholesterol?
  9. IGF-II (insulin-like growth factors-2) can enhance KCC1 (KC1 co-transport-1) gene expression in cervical cancer cells through signal transduction pathways
    Title: The up-regulation of KCC1 gene expression in cervical cancer cells by IGF-II through the ERK1/2MAPK and PI3K/AKT pathways and its significance.
  10. human osteoblasts express functional K-Cl cotransporters in their cell membrane that seem to be able to induce the indirect activation of volume-sensitive Cl- channels by KCl through an increase in intracellular ions, water influx and cell swelling.
    Title: Influence of K-Cl cotransporter activity on activation of volume-sensitive Cl- channels in human osteoblasts.
Submit: New GeneRIF Correction See all GeneRIFs (14)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
Biological insights from 108 schizophrenia-associated genetic loci.
EBI GWAS Catalog

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Clone Names

  • FLJ17069, FLJ40489

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables ATP binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables potassium:chloride symporter activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables potassium:chloride symporter activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables potassium:chloride symporter activity ISS
Inferred from Sequence or Structural Similarity
more info
  
enables potassium:chloride symporter activity TAS
Traceable Author Statement
more info
  
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables protein kinase binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in cell volume homeostasis IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in chemical synaptic transmission IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in chloride ion homeostasis IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in chloride ion homeostasis ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in chloride transmembrane transport IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in monoatomic ion transport TAS
Traceable Author Statement
more info
  
involved_in potassium ion homeostasis IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in potassium ion homeostasis ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in potassium ion import across plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in potassium ion import across plasma membrane ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in potassium ion transmembrane transport ISS
Inferred from Sequence or Structural Similarity
more info
  
Component Evidence Code Pubs
located_in lysosomal membrane HDA PubMed 
located_in membrane TAS
Traceable Author Statement
more info
 PubMed 
is_active_in plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in plasma membrane ISS
Inferred from Sequence or Structural Similarity
more info
  
located_in plasma membrane TAS
Traceable Author Statement
more info
  
located_in synapse IEA
Inferred from Electronic Annotation
more info
  

General protein information

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Preferred Names
solute carrier family 12 member 4
Names
electroneutral potassium-chloride cotransporter 1
erythroid K-Cl cotransporter 1
potassium/chloride cotransporter 1
solute carrier family 12 (potassium/chloride transporter), member 4
solute carrier family 12 (potassium/chloride transporters), member 4

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_033098.1 RefSeqGene

    Range
    5058..30221
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001145961.2 → NP_001139433.1  solute carrier family 12 member 4 isoform b

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) uses an alternate in-frame splice site in the 3' coding region compared to variant 1. This results in a shorter protein (isoform b) compared to isoform a.
    Source sequence(s)
    AI368074, AK293906, AK310027, BC021193, CF272417, DC321966
    UniProtKB/TrEMBL
    B4DF30
    Conserved Domains (1) summary
    TIGR00930
    Location:42 → 1079
    2a30; K-Cl cotransporter

  2. NM_001145962.1 → NP_001139434.1  solute carrier family 12 member 4 isoform c

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) lacks an alternate exon in the 5' coding region, and initiates translation at an alternate upstream start codon, compared to variant 1. The encoded isoform (c) has a distinct N-terminus and is longer than isoform a.
    Source sequence(s)
    AF047338, AI368074, AK293956, AK310027, CF272417, DC321966
    UniProtKB/TrEMBL
    B4DF30
    Conserved Domains (1) summary
    TIGR00930
    Location:70 → 1087
    2a30; K-Cl cotransporter

  3. NM_001145963.2 → NP_001139435.1  solute carrier family 12 member 4 isoform d

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) contains an alternate 5' exon which includes a translational start codon, compared to variant 1. The encoded isoform (d) has a distinct N-terminus and is shorter than isoform a.
    Source sequence(s)
    AI368074, AK310027, AK316415, CF272417, DC402650
    Consensus CDS
    CCDS54030.1
    UniProtKB/TrEMBL
    B4DF30
    Related
    ENSP00000445962.2, ENST00000537830.6
    Conserved Domains (1) summary
    TIGR00930
    Location:36 → 1079
    2a30; K-Cl cotransporter

  4. NM_001145964.2 → NP_001139436.1  solute carrier family 12 member 4 isoform e

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5) contains an alternate 5' exon which includes a translational start codon, compared to variant 1. The encoded isoform (e) has a distinct N-terminus and is shorter than isoform a.
    Source sequence(s)
    AI368074, AK299042, AK310027, CF272417, DC333904
    Consensus CDS
    CCDS54031.1
    UniProtKB/TrEMBL
    B4DF30
    Related
    ENSP00000438334.2, ENST00000541864.7
    Conserved Domains (1) summary
    TIGR00930
    Location:11 → 1054
    2a30; K-Cl cotransporter

  5. NM_005072.5 → NP_005063.1  solute carrier family 12 member 4 isoform a

    See identical proteins and their annotated locations for NP_005063.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the longest transcript and encodes isoform a.
    Source sequence(s)
    AF047338, AI368074, AK310027, CF272417, DC321966
    Consensus CDS
    CCDS10855.1
    UniProtKB/Swiss-Prot
    B4DF69, B4DR04, B4DZ82, B7ZAV0, F5H066, F5H0S9, F5H3C0, O60632, O75893, Q13953, Q96LD5, Q9UP95
    UniProtKB/TrEMBL
    B4DF30
    Related
    ENSP00000318557.3, ENST00000316341.8
    Conserved Domains (1) summary
    TIGR00930
    Location:42 → 1085
    2a30; K-Cl cotransporter

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000016.10 Reference GRCh38.p14 Primary Assembly

    Range
    67943474..67968694 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060940.1 Alternate T2T-CHM13v2.0

    Range
    73739247..73764467 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q9UP95.2 GenPept UniProtKB/Swiss-Prot:Q9UP95

Gene LinkOut

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