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

Summary

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: mouse all
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Genomic context

Location:: 16q22.1

Exon count:: 26

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	16	NC_000016.10 (67943474..67968694, complement)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	16	NC_060940.1 (73739247..73764467, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	16	NC_000016.9 (67977377..68002597, complement)

Chromosome 16 - NC_000016.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

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Expression

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See details

Project title: 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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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

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.
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.
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.
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.
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.
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.
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.
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?
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.
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 EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH70676 (e-PCR)
- UniSTS:14116

RH44404 (e-PCR)
- UniSTS:48741

RH77895 (e-PCR)
- UniSTS:34407

D7S3207 (e-PCR)
- UniSTS:229489

ksks15 (e-PCR)
- UniSTS:514176

SLC12A4 (e-PCR)
- UniSTS:503442

RH70236 (e-PCR)
- UniSTS:51614

SLC12A4_2007 (e-PCR)
- UniSTS:281001

RH79953 (e-PCR)
- UniSTS:84909

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	IDA Inferred from Direct Assay more info	PubMed
enables ammonium transmembrane transporter activity	ISS Inferred from Sequence or Structural Similarity more info
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 ammonium import across plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
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 transmembrane transport	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
located_in lysosomal membrane	HDA more info	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

NG_033098.1 RefSeqGene

Range

5058..30221

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

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
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
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
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
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