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SLC12A3 solute carrier family 12 member 3 [ Homo sapiens (human) ]

Gene ID: 6559, updated on 11-Apr-2024

Summary

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Official Symbol
SLC12A3provided by HGNC
Official Full Name
solute carrier family 12 member 3provided by HGNC
Primary source
HGNC:HGNC:10912
See related
Ensembl:ENSG00000070915 MIM:600968; AllianceGenome:HGNC:10912
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
NCC; TSC; NCCT
Summary
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]
Expression
Restricted expression toward kidney (RPKM 65.2) See more
Orthologs
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Genomic context

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See SLC12A3 in Genome Data Viewer
Location:
16q13
Exon count:
26
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 16 NC_000016.10 (56865207..56915850)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 16 NC_060940.1 (62661526..62712168)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 16 NC_000016.9 (56899119..56949762)

Chromosome 16 - NC_000016.10Genomic Context describing neighboring genes Neighboring gene Sharpr-MPRA regulatory region 1622 Neighboring gene nucleoporin 93 Neighboring gene ReSE screen-validated silencer GRCh37_chr16:56885802-56886009 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10853 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10854 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:56901109-56901693 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:56901694-56902278 Neighboring gene microRNA 138-2 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10855 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10856 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:56908501-56909437 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:56910353-56910852 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:56926577-56927308 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10857 Neighboring gene ReSE screen-validated silencer GRCh37_chr16:56937172-56937352 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:56937981-56938489 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr16:56946332-56947531 Neighboring gene ribosomal protein S24 pseudogene 17 Neighboring gene microRNA 6863 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:56965546-56966100 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:56966101-56966655 Neighboring gene Sharpr-MPRA regulatory region 13851 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10862 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7516 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7517 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7518 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10863 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 10864 Neighboring gene uncharacterized LOC124903811 Neighboring gene homocysteine inducible ER protein with ubiquitin like domain 1

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Bibliography

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Related articles in PubMed

  1. Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter. Fan M, et al. Nature, 2023 Feb. PMID 36792826, Free PMC Article
  2. Minigene splicing assays reveal new insights into exonic variants of the SLC12A3 gene in Gitelman syndrome. Shi X, et al. Mol Genet Genomic Med, 2023 Apr. PMID 36597580, Free PMC Article
  3. Cryo-EM structure of the human sodium-chloride cotransporter NCC. Nan J, et al. Sci Adv, 2022 Nov 11. PMID 36351028, Free PMC Article
  4. Detecting pathogenic deep intronic variants in Gitelman syndrome. Rossanti R, et al. Am J Med Genet A, 2022 Sep. PMID 35785516
  5. A novel mutation of SLC12A3 gene causing Gitelman syndrome. De Silva N, et al. SAGE Open Med Case Rep, 2022. PMID 35693921, Free PMC Article

See all (162) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. From Fish Physiology to Human Disease: The Discovery of the NCC, NKCC2, and the Cation-Coupled Chloride Cotransporters.
    Title: From Fish Physiology to Human Disease: The Discovery of the NCC, NKCC2, and the Cation-Coupled Chloride Cotransporters.
  2. Spectrum of variants in a large Chinese Gitelman syndrome cohort.
    Title: Spectrum of variants in a large Chinese Gitelman syndrome cohort.
  3. Novel SLC12A3 gene mutations and clinical characteristics in two pedigrees with Gitelman syndrome.
    Title: Novel SLC12A3 gene mutations and clinical characteristics in two pedigrees with Gitelman syndrome.
  4. Novel heterozygous mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome: A care-compliant case report.
    Title: Novel heterozygous mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome: A care-compliant case report.
  5. Minigene splicing assays reveal new insights into exonic variants of the SLC12A3 gene in Gitelman syndrome.
    Title: Minigene splicing assays reveal new insights into exonic variants of the SLC12A3 gene in Gitelman syndrome.
  6. Upregulation of SLC12A3 and SLC12A9 Mediated by the HCP5/miR-140-5p Axis Confers Aggressiveness and Unfavorable Prognosis in Uveal Melanoma.
    Title: Upregulation of SLC12A3 and SLC12A9 Mediated by the HCP5/miR-140-5p Axis Confers Aggressiveness and Unfavorable Prognosis in Uveal Melanoma.
  7. Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.
    Title: Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.
  8. R158Q and G212S, novel pathogenic compound heterozygous variants in SLC12A3 of Gitelman syndrome.
    Title: R158Q and G212S, novel pathogenic compound heterozygous variants in SLC12A3 of Gitelman syndrome.
  9. Multiple molecular mechanisms are involved in the activation of the kidney sodium-chloride cotransporter by hypokalemia.
    Title: Multiple molecular mechanisms are involved in the activation of the kidney sodium-chloride cotransporter by hypokalemia.
  10. Detecting pathogenic deep intronic variants in Gitelman syndrome.
    Title: Detecting pathogenic deep intronic variants in Gitelman syndrome.
Submit: New GeneRIF Correction See all GeneRIFs (131)

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

Associated conditions

Description Tests
Familial hypokalemia-hypomagnesemia
MedGen: C0268450 OMIM: 263800 GeneReviews: Not available
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EBI GWAS Catalog

Description
Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci.
EBI GWAS Catalog
Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: Genomewide analysis among 18 245 initially healthy women from the Women's Genome Health Study.
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

  • FLJ96318

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables ATP binding IEA
Inferred from Electronic Annotation
more info
  
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables salt transmembrane transporter activity IEA
Inferred from Electronic Annotation
more info
  
enables sodium:chloride symporter activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables sodium:chloride symporter activity TAS
Traceable Author Statement
more info
  
enables sodium:potassium:chloride symporter activity IBA
Inferred from Biological aspect of Ancestor
more info
  
Process Evidence Code Pubs
involved_in cell volume homeostasis IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in cellular response to inorganic substance IEA
Inferred from Electronic Annotation
more info
  
involved_in chloride ion homeostasis IBA
Inferred from Biological aspect of Ancestor
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 import across plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in renal sodium ion absorption IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in response to aldosterone IEA
Inferred from Electronic Annotation
more info
  
involved_in response to dietary excess IEA
Inferred from Electronic Annotation
more info
  
involved_in signal transduction IEA
Inferred from Electronic Annotation
more info
  
involved_in sodium ion homeostasis IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in sodium ion transmembrane transport IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in sodium ion transmembrane transport ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in sodium ion transport ISS
Inferred from Sequence or Structural Similarity
more info
  
Component Evidence Code Pubs
is_active_in apical plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in apical plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in apical plasma membrane ISS
Inferred from Sequence or Structural Similarity
more info
  
located_in cytosol IEA
Inferred from Electronic Annotation
more info
  
located_in extracellular exosome HDA PubMed 
located_in extracellular exosome IDA
Inferred from Direct Assay
more info
 PubMed 
located_in membrane TAS
Traceable Author Statement
more info
 PubMed 
is_active_in plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in plasma membrane TAS
Traceable Author Statement
more info
  

General protein information

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Preferred Names
solute carrier family 12 member 3
Names
Na-Cl cotransporter
Na-Cl symporter
NaCl electroneutral thiazide-sensitive cotransporter
sodium-chloride co-transporter
solute carrier family 12 (sodium/chloride transporter), member 3
thiazide-sensitive Na-Cl cotransporter
thiazide-sensitive sodium-chloride cotransporter

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_009386.2 RefSeqGene

    Range
    5001..55644
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_000339.3 → NP_000330.3  solute carrier family 12 member 3 isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
    Source sequence(s)
    AC012181
    Consensus CDS
    CCDS10770.1
    Related
    ENSP00000402152.2, ENST00000438926.6
    Conserved Domains (1) summary
    TIGR00930
    Location:59 → 1029
    2a30; K-Cl cotransporter

  2. NM_001126107.2 → NP_001119579.2  solute carrier family 12 member 3 isoform 2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) uses an alternate in-frame splice site in the 5' coding region, compared to variant 1, resulting in a protein (isoform 2) that is 1 aa shorter than isoform 1.
    Source sequence(s)
    AC012181
    Consensus CDS
    CCDS45491.1
    Related
    ENSP00000457552.1, ENST00000566786.5
    Conserved Domains (1) summary
    TIGR00930
    Location:59 → 1028
    2a30; K-Cl cotransporter

  3. NM_001126108.2 → NP_001119580.2  solute carrier family 12 member 3 isoform 3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) uses an alternate in-frame splice site in the 3' coding region, compared to variant 1, resulting in a protein (isoform 3) that is 9 aa shorter than isoform 1.
    Source sequence(s)
    AC012181
    Consensus CDS
    CCDS58464.1
    UniProtKB/Swiss-Prot
    A8MSJ2, C9JNN9, P55017
    Related
    ENSP00000456149.2, ENST00000563236.6
    Conserved Domains (1) summary
    TIGR00930
    Location:59 → 1020
    2a30; K-Cl cotransporter

  4. NM_001410896.1 → NP_001397825.1  solute carrier family 12 member 3 isoform 4

    Status: REVIEWED

    Source sequence(s)
    AC012181
    Consensus CDS
    CCDS92165.1
    UniProtKB/TrEMBL
    J3QSS1
    Related
    ENSP00000262502.5, ENST00000262502.5

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

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
    56865207..56915850
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060940.1 Alternate T2T-CHM13v2.0

    Range
    62661526..62712168
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P55017.3 GenPept UniProtKB/Swiss-Prot:P55017

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