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SLC4A4 solute carrier family 4 member 4 [ Homo sapiens (human) ]

Gene ID: 8671, updated on 3-Nov-2024

Summary

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Official Symbol
SLC4A4provided by HGNC
Official Full Name
solute carrier family 4 member 4provided by HGNC
Primary source
HGNC:HGNC:11030
See related
Ensembl:ENSG00000080493 MIM:603345; AllianceGenome:HGNC:11030
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
KNBC; NBC1; NBC2; pNBC; HNBC1; NBCe1; PRTAO; hhNMC; kNBC1; SLC4A5; NBCe1-A
Summary
This gene encodes a sodium bicarbonate cotransporter (NBC) involved in the regulation of bicarbonate secretion and absorption and intracellular pH. Mutations in this gene are associated with proximal renal tubular acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]
Expression
Biased expression in kidney (RPKM 56.0), pancreas (RPKM 31.5) and 12 other tissues See more
Orthologs
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Genomic context

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See SLC4A4 in Genome Data Viewer
Location:
4q13.3
Exon count:
37
Annotation release Status Assembly Chr Location
RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 4 NC_000004.12 (71062660..71572083)
RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 4 NC_060928.1 (74404936..74914352)
RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 4 NC_000004.11 (72052482..72437800)

Chromosome 4 - NC_000004.12Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC124900711 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 15472 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 15473 Neighboring gene Sharpr-MPRA regulatory region 2882 Neighboring gene MOB kinase activator 1B Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 15474 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 21603 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:71869952-71870648 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 21605 Neighboring gene ReSE screen-validated silencer GRCh37_chr4:71883900-71884096 Neighboring gene H3K27ac hESC enhancer GRCh37_chr4:71894495-71894995 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:71924658-71925260 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:71925261-71925861 Neighboring gene deoxycytidine kinase Neighboring gene uncharacterized LOC124900712 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr4:72061583-72062135 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr4:72165851-72166352 Neighboring gene probable UDP-sugar transporter protein SLC35A4 Neighboring gene SLC35A4 upstream open reading frame protein-like Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 15475 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 21606 Neighboring gene H3K27ac hESC enhancer GRCh37_chr4:72234371-72234872 Neighboring gene H3K27ac hESC enhancer GRCh37_chr4:72234873-72235372 Neighboring gene MED14-independent group 3 enhancer GRCh37_chr4:72338203-72339402 Neighboring gene lactate dehydrogenase A like 6E, pseudogene Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr4:72458772-72459481 Neighboring gene uncharacterized LOC107986285 Neighboring gene MED14-independent group 3 enhancer GRCh37_chr4:72479894-72481093 Neighboring gene uncharacterized LOC105377271 Neighboring gene MED14-independent group 3 enhancer GRCh37_chr4:72519382-72520581

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. Sequence- or position-specific mutations in the carboxyl-terminal FL motif of the kidney sodium bicarbonate cotransporter (NBC1) disrupt its basolateral targeting and alpha-helical structure. Li HC, et al. J Membr Biol, 2009 Mar. PMID 19294449
  2. The Na(+)/HCO3(-) Co-Transporter SLC4A4 Plays a Role in Growth and Migration of Colon and Breast Cancer Cells. Parks SK, et al. J Cell Physiol, 2015 Aug. PMID 25612232
  3. Interplay between disulfide bonding and N-glycosylation defines SLC4 Na+-coupled transporter extracellular topography. Zhu Q, et al. J Biol Chem, 2015 Feb 27. PMID 25568315, Free PMC Article
  4. Identification of membrane topography of the electrogenic sodium bicarbonate cotransporter pNBC1 by in vitro transcription/translation. Tatishchev S, et al. Biochemistry, 2003 Jan 28. PMID 12534288
  5. Phosphorylation-induced modulation of pNBC1 function: distinct roles for the amino- and carboxy-termini. Gross E, et al. J Physiol, 2003 Jun 15. PMID 12730338, Free PMC Article

See all (111) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer.
    Title: SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer.
  2. Distal renal tubular acidosis, autoimmune thyroiditis, enamel hypomaturation, and tooth agenesis caused by homozygosity of a novel double-nucleotide substitution in SLC4A4.
    Title: Distal renal tubular acidosis, autoimmune thyroiditis, enamel hypomaturation, and tooth agenesis caused by homozygosity of a novel double-nucleotide substitution in SLC4A4.
  3. Extracellular vesicles derived from cancer-associated fibroblast carries miR-224-5p targeting SLC4A4 to promote the proliferation, invasion and migration of colorectal cancer cells.
    Title: Extracellular vesicles derived from cancer-associated fibroblast carries miR-224-5p targeting SLC4A4 to promote the proliferation, invasion and migration of colorectal cancer cells.
  4. A novel I551F variant of the Na(+)/HCO3(-) cotransporter NBCe1-A shows reduced cell surface expression, resulting in diminished transport activity.
    Title: A novel I551F variant of the Na(+)/HCO(3)(-) cotransporter NBCe1-A shows reduced cell surface expression, resulting in diminished transport activity.
  5. Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3.
    Title: Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3.
  6. Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic beta cell function in type 2 diabetes.
    Title: Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes.
  7. Prognostic Value of SLC4A4 and its Correlation with Immune Infiltration in Colon Adenocarcinoma.
    Title: Prognostic Value of SLC4A4 and its Correlation with Immune Infiltration in Colon Adenocarcinoma.
  8. hsa_circRNA_001587 upregulates SLC4A4 expression to inhibit migration, invasion, and angiogenesis of pancreatic cancer cells via binding to microRNA-223.
    Title: hsa_circRNA_001587 upregulates SLC4A4 expression to inhibit migration, invasion, and angiogenesis of pancreatic cancer cells via binding to microRNA-223.
  9. SLC4A4 expression correlated negatively with miR-223-3p expression in patient samples. Given that miR-223-3p suppressed the SLC4A4/KRAS axis, miR-223-3p gene therapy could be an effective treatment for renal cancer.
    Title: MiR-223-3p promotes cell proliferation and metastasis by downregulating SLC4A4 in clear cell renal cell carcinoma.
  10. the sodium bicarbonate cotransporter NBCe1-B is expressed in rat and human thyroid
    Title: Expression, Localization, and Regulation of the Sodium Bicarbonate Cotransporter NBCe1 in the Thyroid.
Submit: New GeneRIF Correction See all GeneRIFs (69)

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
Autosomal recessive proximal renal tubular acidosis
MedGen: C1970309 OMIM: 604278 GeneReviews: Not available
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EBI GWAS Catalog

Description
Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants.
EBI GWAS Catalog
Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
EBI GWAS Catalog
Impact of ancestry and common genetic variants on QT interval in African Americans.
EBI GWAS Catalog
Meta-analysis of genome-wide association studies in multiethnic Asians identifies two loci for age-related nuclear cataract.
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

  • DKFZp781H1314

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables identical protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables monoatomic anion transmembrane transporter activity IEA
Inferred from Electronic Annotation
more info
  
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables sodium:bicarbonate symporter activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables sodium:bicarbonate symporter activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables sodium:bicarbonate symporter activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables sodium:bicarbonate symporter activity TAS
Traceable Author Statement
more info
 PubMed 
enables solute:inorganic anion antiporter activity IEA
Inferred from Electronic Annotation
more info
  
enables symporter activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
Process Evidence Code Pubs
involved_in bicarbonate transport IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in bicarbonate transport IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in bicarbonate transport IEA
Inferred from Electronic Annotation
more info
  
involved_in bicarbonate transport IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in bicarbonate transport TAS
Traceable Author Statement
more info
  
involved_in inorganic anion transport IEA
Inferred from Electronic Annotation
more info
  
involved_in monoatomic anion transmembrane transport IEA
Inferred from Electronic Annotation
more info
  
acts_upstream_of positive regulation of glycolytic process IGI
Inferred from Genetic Interaction
more info
 PubMed 
acts_upstream_of positive regulation of glycolytic process ISS
Inferred from Sequence or Structural Similarity
more info
 PubMed 
involved_in regulation of intracellular pH IBA
Inferred from Biological aspect of Ancestor
more info
  
acts_upstream_of regulation of intracellular pH IDA
Inferred from Direct Assay
more info
 PubMed 
acts_upstream_of regulation of intracellular pH IGI
Inferred from Genetic Interaction
more info
 PubMed 
involved_in regulation of intracellular pH IMP
Inferred from Mutant Phenotype
more info
 PubMed 
acts_upstream_of regulation of intracellular pH ISS
Inferred from Sequence or Structural Similarity
more info
 PubMed 
acts_upstream_of regulation of membrane potential IDA
Inferred from Direct Assay
more info
 PubMed 
acts_upstream_of regulation of membrane potential ISS
Inferred from Sequence or Structural Similarity
more info
 PubMed 
involved_in sodium ion export across plasma membrane IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in sodium ion transmembrane transport IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in sodium ion transmembrane transport IEA
Inferred from Electronic Annotation
more info
  
involved_in sodium ion transport IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in transmembrane transport IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in transmembrane transport IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in transport across blood-brain barrier NAS
Non-traceable Author Statement
more info
 PubMed 
Component Evidence Code Pubs
is_active_in basolateral plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in basolateral plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in basolateral plasma membrane IMP
Inferred from Mutant Phenotype
more info
 PubMed 
located_in cell surface IDA
Inferred from Direct Assay
more info
 PubMed 
located_in extracellular exosome HDA PubMed 
is_active_in membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in membrane IDA
Inferred from Direct Assay
more info
 PubMed 
is_active_in plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
  
is_active_in plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in plasma membrane IMP
Inferred from Mutant Phenotype
more info
 PubMed 
located_in plasma membrane RCA
inferred from Reviewed Computational Analysis
more info
 PubMed 
located_in plasma membrane TAS
Traceable Author Statement
more info
  

General protein information

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Preferred Names
electrogenic sodium bicarbonate cotransporter 1
Names
Na(+)/HCO3(-) cotransporter
kidney type Na+/HCO3- cotransporter
pancreatic sodium bicarbonate cotransporter
sodium bicarbonate cotransporter 1 (sodium bicarbonate cotransporter, kidney; sodium bicarbonate cotransporter, pancreas)
solute carrier family 4 (sodium bicarbonate cotransporter), member 4
solute carrier family 4, sodium bicarbonate cotransporter, member 4, brain type
solute carrier family 4, sodium bicarbonate cotransporter, member 5

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_012653.2 RefSeqGene

    Range
    129107..514425
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001098484.3 → NP_001091954.1  electrogenic sodium bicarbonate cotransporter 1 isoform 1

    See identical proteins and their annotated locations for NP_001091954.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the longest transcript.
    Source sequence(s)
    AC019089, AC079230, AC096713, AC110783
    Consensus CDS
    CCDS43236.1
    UniProtKB/Swiss-Prot
    C4B714, O15153, Q8NEJ2, Q9H262, Q9NRZ1, Q9UIC0, Q9UIC1, Q9UP50, Q9Y6R1
    UniProtKB/TrEMBL
    A0A8V8TNB1
    Related
    ENSP00000264485.5, ENST00000264485.11
    Conserved Domains (1) summary
    TIGR00834
    Location:109 → 1003
    ae; anion exchange protein

  2. NM_001134742.2 → NP_001128214.1  electrogenic sodium bicarbonate cotransporter 1 isoform 3

    See identical proteins and their annotated locations for NP_001128214.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) lacks an alternate exon in the 3' coding region that results in a frameshift, compared to variant 1. It encodes isoform 3 which has a longer and distinct C-terminus compared to isoform 1.
    Source sequence(s)
    AC019089, AC079230, AC096713, AC110783
    Consensus CDS
    CCDS47071.1
    UniProtKB/TrEMBL
    A0A8V8TNB1, A5JJ20
    Related
    ENSP00000393557.1, ENST00000425175.5
    Conserved Domains (3) summary
    TIGR00834
    Location:109 → 1003
    ae; anion exchange protein
    pfam00955
    Location:436 → 955
    HCO3_cotransp; HCO3- transporter family
    pfam07565
    Location:137 → 387
    Band_3_cyto; Band 3 cytoplasmic domain

  3. NM_003759.4 → NP_003750.1  electrogenic sodium bicarbonate cotransporter 1 isoform 2

    See identical proteins and their annotated locations for NP_003750.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) differs in the 5' UTR and coding region, compared to variant 1. These differences cause translation initiation at a downstream AUG and an isoform (2) with a shorter and distinct N-terminus compared to isoform 1.
    Source sequence(s)
    AC019089, AC079230, AC110783
    Consensus CDS
    CCDS3549.1
    UniProtKB/TrEMBL
    A0A8V8TNB1
    Related
    ENSP00000344272.3, ENST00000340595.4
    Conserved Domains (1) summary
    TIGR00834
    Location:65 → 959
    ae; anion exchange protein

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_000004.12 Reference GRCh38.p14 Primary Assembly

    Range
    71062660..71572083
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_024454268.2 → XP_024310036.1  electrogenic sodium bicarbonate cotransporter 1 isoform X2

    UniProtKB/TrEMBL
    A0A8V8TNB1
    Related
    ENSP00000513771.1, ENST00000698522.1
    Conserved Domains (1) summary
    TIGR00834
    Location:114 → 1008
    ae; anion exchange protein

  2. XM_024454269.2 → XP_024310037.1  electrogenic sodium bicarbonate cotransporter 1 isoform X2

    UniProtKB/TrEMBL
    A0A8V8TNB1
    Conserved Domains (1) summary
    TIGR00834
    Location:114 → 1008
    ae; anion exchange protein

  3. XM_024454270.2 → XP_024310038.1  electrogenic sodium bicarbonate cotransporter 1 isoform X3

    UniProtKB/Swiss-Prot
    C4B714, O15153, Q8NEJ2, Q9H262, Q9NRZ1, Q9UIC0, Q9UIC1, Q9UP50, Q9Y6R1
    UniProtKB/TrEMBL
    A0A8V8TNB1
    Related
    ENSP00000497468.1, ENST00000649996.1
    Conserved Domains (1) summary
    TIGR00834
    Location:109 → 1003
    ae; anion exchange protein

  4. XM_024454272.2 → XP_024310040.1  electrogenic sodium bicarbonate cotransporter 1 isoform X3

    UniProtKB/Swiss-Prot
    C4B714, O15153, Q8NEJ2, Q9H262, Q9NRZ1, Q9UIC0, Q9UIC1, Q9UP50, Q9Y6R1
    UniProtKB/TrEMBL
    A0A8V8TNB1
    Conserved Domains (1) summary
    TIGR00834
    Location:109 → 1003
    ae; anion exchange protein

  5. XM_024454271.2 → XP_024310039.1  electrogenic sodium bicarbonate cotransporter 1 isoform X3

    UniProtKB/Swiss-Prot
    C4B714, O15153, Q8NEJ2, Q9H262, Q9NRZ1, Q9UIC0, Q9UIC1, Q9UP50, Q9Y6R1
    UniProtKB/TrEMBL
    A0A8V8TNB1
    Conserved Domains (1) summary
    TIGR00834
    Location:109 → 1003
    ae; anion exchange protein

  6. XM_024454267.2 → XP_024310035.1  electrogenic sodium bicarbonate cotransporter 1 isoform X1

    UniProtKB/TrEMBL
    A0A8V8TNB1
    Conserved Domains (1) summary
    TIGR00834
    Location:140 → 1034
    ae; anion exchange protein

  7. XM_017008792.2 → XP_016864281.1  electrogenic sodium bicarbonate cotransporter 1 isoform X4

    UniProtKB/TrEMBL
    A0A8V8TNB1

  8. XM_047416348.1 → XP_047272304.1  electrogenic sodium bicarbonate cotransporter 1 isoform X7

  9. XM_017008793.2 → XP_016864282.1  electrogenic sodium bicarbonate cotransporter 1 isoform X5

  10. XM_011532390.3 → XP_011530692.1  electrogenic sodium bicarbonate cotransporter 1 isoform X6

    Conserved Domains (2) summary
    pfam00955
    Location:250 → 769
    HCO3_cotransp; HCO3- transporter family
    pfam07565
    Location:59 → 201
    Band_3_cyto; Band 3 cytoplasmic domain

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060928.1 Alternate T2T-CHM13v2.0

    Range
    74404936..74914352
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054351152.1 → XP_054207127.1  electrogenic sodium bicarbonate cotransporter 1 isoform X2

  2. XM_054351153.1 → XP_054207128.1  electrogenic sodium bicarbonate cotransporter 1 isoform X2

  3. XM_054351155.1 → XP_054207130.1  electrogenic sodium bicarbonate cotransporter 1 isoform X3

    UniProtKB/Swiss-Prot
    C4B714, O15153, Q8NEJ2, Q9H262, Q9NRZ1, Q9UIC0, Q9UIC1, Q9UP50, Q9Y6R1

  4. XM_054351154.1 → XP_054207129.1  electrogenic sodium bicarbonate cotransporter 1 isoform X3

    UniProtKB/Swiss-Prot
    C4B714, O15153, Q8NEJ2, Q9H262, Q9NRZ1, Q9UIC0, Q9UIC1, Q9UP50, Q9Y6R1

  5. XM_054351156.1 → XP_054207131.1  electrogenic sodium bicarbonate cotransporter 1 isoform X3

    UniProtKB/Swiss-Prot
    C4B714, O15153, Q8NEJ2, Q9H262, Q9NRZ1, Q9UIC0, Q9UIC1, Q9UP50, Q9Y6R1

  6. XM_054351151.1 → XP_054207126.1  electrogenic sodium bicarbonate cotransporter 1 isoform X1

  7. XM_054351157.1 → XP_054207132.1  electrogenic sodium bicarbonate cotransporter 1 isoform X4

  8. XM_054351158.1 → XP_054207133.1  electrogenic sodium bicarbonate cotransporter 1 isoform X5

  9. XM_054351159.1 → XP_054207134.1  electrogenic sodium bicarbonate cotransporter 1 isoform X6

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q9Y6R1.1 GenPept UniProtKB/Swiss-Prot:Q9Y6R1

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