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

Summary

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
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; 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: mouse all

Genomic context

Location:: 4q13.3

Exon count:: 36

Annotation release	Status	Assembly	Chr	Location
109.20200522	current	GRCh38.p13 (GCF_000001405.39)	4	NC_000004.12 (71062646..71572083)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	4	NC_000004.11 (72053003..72437804)

Chromosome 4 - NC_000004.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

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?

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.
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.
The SLC4A4 transcript was almost undetectable in the proband.
Title: SLC4A4 compound heterozygous mutations in exon-intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner's syndrome: a case report.
In this retrospective case series, we highlight our experience with children referred to a pediatric ophthalmologist who were found to harbor underlying biallelic SLC4A4 mutations.
Title: Pediatric primary calcific band keratopathy with or without glaucoma from biallelic SLC4A4 mutations.
A novel mechanism for variable phenotypic expressivity in band-shaped corneal dystrophy mediated by an AU-rich element (ARE)-creating mutation in SLC4A4 in three unrelated consanguineous families has been described.
Title: A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation.
the structure of the membrane domain dimer of human NBCe1 at 3.9 A resolution by cryo electron microscopy, was determined.
Title: CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1.
Common variants in the SLC4A4 gene might contribute to the variation of blood pressure responses to dietary sodium intake in Han Chinese population.
Title: Common variants in the Na(+)-coupled bicarbonate transporter genes and salt sensitivity of blood pressure: the GenSalt study.
R510H and Q913R identified in a patient with proximal renal tubular acidosis. Mutant proteins exhibit substantial intracellular retention when expressed in mammalian renal cell lines. Q913R is associated with an unusual HCO3- independent anion-leak in Xenopus oocytes.
Title: A novel mutant Na<sup>+</sup> /HCO3<sup>-</sup> cotransporter NBCe1 in a case of compound-heterozygous inheritance of proximal renal tubular acidosis.
miR-224 was significantly downregulated as ameloblasts differentiated, in parallel with upregulation of SLC4A4 and CFTR.
Title: MicroRNA 224 Regulates Ion Transporter Expression in Ameloblasts To Coordinate Enamel Mineralization.
The R298S is a temperature-sensitive mutation in NBCe1-A that results in instability of the colloidal system leading to abnormal aggregation.
Title: Rescue of the temperature-sensitive, autosomal-recessive mutation R298S in the sodium-bicarbonate cotransporter NBCe1-A characterized by a weakened dimer and abnormal aggregation.

Submit: New GeneRIF Correction See all GeneRIFs (61)

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
Renal tubular acidosis, proximal, with ocular abnormalities and mental retardation MedGen: C1970309 OMIM: 604278 GeneReviews: Not available	Compare labs

NHGRI GWAS Catalog

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

D4S2931 (e-PCR), detects polymorphism
- UniSTS:50945

SHGC-79648 (e-PCR)
- UniSTS:101405

G16764 (e-PCR)
- UniSTS:70215

D4S1543 (e-PCR), detects polymorphism
- UniSTS:52557

D4S1509 (e-PCR)
- UniSTS:62032

G17822 (e-PCR)
- UniSTS:66651

SHGC-147750 (e-PCR)
- UniSTS:175985

PMC209339P1 (e-PCR)
- UniSTS:271988

SHGC-53498 (e-PCR)
- UniSTS:78976

D4S1543 (e-PCR), detects polymorphism
- UniSTS:78236

SHGC-83657 (e-PCR)
- UniSTS:95910

RH121043 (e-PCR)
- UniSTS:132263

RH123210 (e-PCR)
- UniSTS:135594

SHGC-83779 (e-PCR)
- UniSTS:95922

SLC4A4_3914 (e-PCR)
- UniSTS:462546

SHGC-103649 (e-PCR)
- UniSTS:168916

AW527043 (e-PCR)
- UniSTS:245992

SHGC-100544 (e-PCR)
- UniSTS:170481

Homology

Homologs of the SLC4A4 gene: The SLC4A4 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, S.cerevisiae, K.lactis, E.gossypii, S.pombe, M.oryzae, N.crassa, A.thaliana, and frog.
Orthologs from Annotation Pipeline: 302 organisms have orthologs with human gene SLC4A4
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
inorganic anion exchanger activity	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed
sodium:bicarbonate symporter activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
sodium:bicarbonate symporter activity	IMP Inferred from Mutant Phenotype more info	PubMed
sodium:bicarbonate symporter activity	TAS Traceable Author Statement more info	PubMed
symporter activity	IMP Inferred from Mutant Phenotype more info	PubMed

Process	Evidence Code	Pubs
anion transmembrane transport	IEA Inferred from Electronic Annotation more info
bicarbonate transport	IBA Inferred from Biological aspect of Ancestor more info	PubMed
bicarbonate transport	IDA Inferred from Direct Assay more info	PubMed
bicarbonate transport	IMP Inferred from Mutant Phenotype more info	PubMed
bicarbonate transport	TAS Traceable Author Statement more info
inorganic anion transport	IEA Inferred from Electronic Annotation more info
positive regulation of glycolytic process	IGI Inferred from Genetic Interaction more info	PubMed
positive regulation of glycolytic process	ISS Inferred from Sequence or Structural Similarity more info	PubMed
regulation of intracellular pH	IBA Inferred from Biological aspect of Ancestor more info	PubMed
regulation of intracellular pH	IDA Inferred from Direct Assay more info	PubMed
regulation of intracellular pH	IGI Inferred from Genetic Interaction more info	PubMed
regulation of intracellular pH	IMP Inferred from Mutant Phenotype more info	PubMed
regulation of intracellular pH	ISS Inferred from Sequence or Structural Similarity more info	PubMed
regulation of membrane potential	IDA Inferred from Direct Assay more info	PubMed
regulation of membrane potential	ISS Inferred from Sequence or Structural Similarity more info	PubMed
sodium ion export across plasma membrane	IMP Inferred from Mutant Phenotype more info	PubMed
sodium ion transmembrane transport	IDA Inferred from Direct Assay more info	PubMed
sodium ion transport	IDA Inferred from Direct Assay more info	PubMed
transmembrane transport	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
basolateral plasma membrane	IDA Inferred from Direct Assay more info	PubMed
cell surface	IDA Inferred from Direct Assay more info	PubMed
extracellular exosome	HDA more info	PubMed
integral component of plasma membrane	TAS Traceable Author Statement more info	PubMed
membrane	IDA Inferred from Direct Assay more info	PubMed
plasma membrane	IDA Inferred from Direct Assay more info	PubMed
plasma membrane	TAS Traceable Author Statement more info
spanning component of plasma membrane	RCA inferred from Reviewed Computational Analysis more info	PubMed

General protein information

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Preferred Names: electrogenic sodium bicarbonate cotransporter 1

Names: Na(+)/HCO3(-) 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

NG_012653.1 RefSeqGene

Range

5001..389802

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

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

Q9Y6R1

UniProtKB/TrEMBL

A0A024RD97

Related

ENSP00000264485.5, ENST00000264485.11

Conserved Domains (1) summary

TIGR00834
Location:109 → 1003

ae; anion exchange protein
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

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
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/Swiss-Prot

Q9Y6R1

Related

ENSP00000344272.3, ENST00000340595.3

Conserved Domains (1) summary

TIGR00834
Location:65 → 959

ae; anion exchange protein

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.

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

Reference GRCh38.p13 Primary Assembly

Genomic

NC_000004.12 Reference GRCh38.p13 Primary Assembly

Range

71062646..71572083

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

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

Conserved Domains (1) summary

TIGR00834
Location:114 → 1008

ae; anion exchange protein
XM_024454268.1 → XP_024310036.1 electrogenic sodium bicarbonate cotransporter 1 isoform X2

Conserved Domains (1) summary

TIGR00834
Location:114 → 1008

ae; anion exchange protein
XM_024454270.1 → XP_024310038.1 electrogenic sodium bicarbonate cotransporter 1 isoform X3

Related

ENSP00000497468.1, ENST00000649996.1

Conserved Domains (1) summary

TIGR00834
Location:109 → 1003

ae; anion exchange protein
XM_024454272.1 → XP_024310040.1 electrogenic sodium bicarbonate cotransporter 1 isoform X3

Conserved Domains (1) summary

TIGR00834
Location:109 → 1003

ae; anion exchange protein
XM_024454271.1 → XP_024310039.1 electrogenic sodium bicarbonate cotransporter 1 isoform X3

Conserved Domains (1) summary

TIGR00834
Location:109 → 1003

ae; anion exchange protein
XM_024454267.1 → XP_024310035.1 electrogenic sodium bicarbonate cotransporter 1 isoform X1

Conserved Domains (1) summary

TIGR00834
Location:140 → 1034

ae; anion exchange protein
XM_017008792.1 → XP_016864281.1 electrogenic sodium bicarbonate cotransporter 1 isoform X4
XM_017008793.1 → XP_016864282.1 electrogenic sodium bicarbonate cotransporter 1 isoform X5
XM_011532390.2 → 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