Details for: SLC26A4

Gene ID: 5172

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: SLC26A4

Ensembl ID: ENSG00000091137

Description: solute carrier family 26 member 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • pvalb GABAergic cortical interneuron CL4023018
    CSI 13.45
    rCSI 16.74%
    PRS 95.85
  • nasal mucosa goblet cell CL0002480
    CSI 8.99
    rCSI 10.43%
    PRS 98.39
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 8.56
    rCSI 30.81%
    PRS 95.68
  • renal beta-intercalated cell CL0002201
    CSI 6.92
    rCSI 16.49%
    PRS 98.93
  • inhibitory interneuron CL0000498
    CSI 6
    rCSI 13.85%
    PRS 96.45
  • GABAergic neuron CL0000617
    CSI 5.93
    rCSI 19.87%
    PRS 94.14
  • sncg GABAergic cortical interneuron CL4023015
    CSI 5.92
    rCSI 9.53%
    PRS 96.26
  • VIP GABAergic cortical interneuron CL4023016
    CSI 5.7
    rCSI 6.81%
    PRS 96.27
  • sst GABAergic cortical interneuron CL4023017
    CSI 4.66
    rCSI 6.01%
    PRS 96.83
  • glutamatergic neuron CL0000679
    CSI 4.63
    rCSI 9.52%
    PRS 94.37
  • retinal pigment epithelial cell CL0002586
    CSI 4.11
    rCSI 8.15%
    PRS 97.76
  • kidney collecting duct intercalated cell CL1001432
    CSI 3.85
    rCSI 27.49%
    PRS 97.15
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 3.42
    rCSI 8.32%
    PRS 95.23
  • tracheal goblet cell CL1000329
    CSI 3.25
    rCSI 7.1%
    PRS 99.18
  • multi-ciliated epithelial cell CL0005012
    CSI 2.86
    rCSI 2.86%
    PRS 97.4
  • bronchial goblet cell CL1000312
    CSI 2.73
    rCSI 10.92%
    PRS 99.51
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 2.58
    rCSI 9.77%
    PRS 95.82
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 2.32
    rCSI 3.89%
    PRS 96.64
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 2.28
    rCSI 4.94%
    PRS 94.29
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.9
    rCSI 2.8%
    PRS 96.4

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [SLC26A4](/details-gene/5172), also known as Pendrin, is a protein-coding gene that functions as a multifunctional anion exchanger. It is a member of the solute carrier family 26 and is primarily involved in the transport of chloride, iodide, and bicarbonate across cellular membranes ([Link](https://doi.org/10.1038/7783), [Link](https://doi.org/10.1152/ajpcell.2000.278.1.c207)). Mutations in [SLC26A4](/details-gene/5172) are the cause of Pendred syndrome, an autosomal recessive disorder characterized by sensorineural hearing loss and goiter ([Link](https://doi.org/10.1038/ng1297-411)). Expression data indicates that while classically studied in the inner ear, thyroid, and kidney, [SLC26A4](/details-gene/5172) shows significant expression in a diverse set of cell types, including specific neuronal populations such as [pvalb GABAergic cortical interneuron](/details-cell/CL4023018), secretory cells like [nasal mucosa goblet cell](/details-cell/CL0002480), and specialized renal cells like the [renal beta-intercalated cell](/details-cell/CL0002201), suggesting a broader role in ion homeostasis across multiple organ systems. ## Cellular Roles and Expression Landscape The expression profile of [SLC26A4](/details-gene/5172) highlights its importance in tissues requiring precise regulation of anion transport and pH. **Overall**, the gene's significance is highest in two distinct cellular contexts: the central nervous system and specialized epithelial tissues. In the nervous system, [SLC26A4](/details-gene/5172) shows a remarkably high cell significance index (CSI) in specific neuronal subtypes, including [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 13.45) and [L5 extratelencephalic projecting glutamatergic cortical neuron](/details-cell/CL4023041) (CSI: 8.56). Its strong presence in various [GABAergic neuron](/details-cell/CL0000617) populations suggests a potential role in modulating inhibitory neurotransmission by regulating intracellular chloride and bicarbonate levels, which are critical for setting the electrochemical gradient for GABA-A receptors. In epithelial and secretory tissues, [SLC26A4](/details-gene/5172) is a key marker for cells involved in fluid and ion secretion. It is highly significant in [nasal mucosa goblet cell](/details-cell/CL0002480) (CSI: 8.99) and [tracheal goblet cell](/details-cell/CL1000329) (CSI: 3.25), where its bicarbonate transport activity may be crucial for hydrating mucus and maintaining airway surface liquid pH. Furthermore, its well-documented role in renal function is confirmed by its high significance in [renal beta-intercalated cell](/details-cell/CL0002201) (CSI: 6.92) and [kidney collecting duct intercalated cell](/details-cell/CL1001432) (CSI: 3.85), where it mediates bicarbonate secretion into the urine, contributing to systemic acid-base balance ([Link](https://doi.org/10.1073/pnas.071516798)). ## Pathways and Molecular Function The functions of [SLC26A4](/details-gene/5172) are centered on its activity as an anion transporter located on the [apical plasma membrane](/details-cell/GO:0016324). Gene Ontology annotations confirm its molecular function as a transporter with [chloride:bicarbonate antiporter activity](/details-cell/GO:0140900), [iodide transmembrane transporter activity](/details-cell/GO:0015111), and [sulfate transmembrane transporter activity](/details-cell/GO:0015116). These activities contribute to several key biological processes, including [inorganic anion transport](/details-cell/GO:0015698), [regulation of ph](/details-cell/GO:0006885), and [sensory perception of sound](/details-cell/GO:0007605). Reactome pathway analysis directly links the gene to human disease, most notably through its involvement in the '[Defective slc26a4 causes pendred syndrome (pds)](https://reactome.org/content/detail/R-HSA-5619046)' pathway. This clinical connection arises from its dual role in iodide transport in the thyroid and ion homeostasis in the inner ear. Its function as an iodide porter is essential for thyroid hormone synthesis ([Link](https://doi.org/10.1210/jcem.87.7.8679)), and its disruption leads to the goiter seen in Pendred syndrome. Concurrently, its role in maintaining the unique ionic composition of the endolymph in the inner ear is critical for hearing, and its dysfunction results in sensorineural deafness. These functions place [SLC26A4](/details-gene/5172) within the broader categories of '[Disorders of transmembrane transporters](https://reactome.org/content/detail/R-HSA-5619115)' and '[Transport of small molecules](https://reactome.org/content/detail/R-HSA-382551)'. ## Research Directions While the role of [SLC26A4](/details-gene/5172) in Pendred syndrome is well-established, its high significance in previously under-appreciated cell types, such as cortical neurons and airway goblet cells, opens new avenues for investigation. ### Proposed Hypotheses 1. **Role in Neuronal Excitability:** The high and specific expression of [SLC26A4](/details-gene/5172) in distinct cortical neurons, such as [pvalb GABAergic cortical interneuron](/details-cell/CL4023018), suggests it is a key regulator of intracellular anion concentration. We hypothesize that [SLC26A4](/details-gene/5172) activity is critical for maintaining the chloride gradient necessary for efficient GABAergic inhibition, and its dysregulation could contribute to network hyperexcitability and neurological disorders like epilepsy. 2. **Function in Mucociliary Clearance:** The prominent expression of [SLC26A4](/details-gene/5172) in [nasal mucosa goblet cell](/details-cell/CL0002480) suggests a role in mucosal immunology and physiology. We hypothesize that [SLC26A4](/details-gene/5172)-mediated bicarbonate secretion into the airway surface liquid is essential for the proper unfolding of mucin polymers and the maintenance of optimal mucus viscosity, thereby playing a critical role in effective mucociliary clearance. ### Experimental Approach To test the role of [SLC26A4](/details-gene/5172) in neuronal function (Hypothesis 1), a cell type-specific knockout mouse model could be developed by crossing a floxed-[SLC26A4](/details-gene/5172) mouse line with a Pvalb-Cre driver line. Brain slices from these conditional knockout mice could be analyzed using whole-cell patch-clamp electrophysiology. The primary readout would be the measurement of the GABA-A reversal potential (E_GABA) in Pvalb-positive interneurons to determine if the loss of [SLC26A4](/details-gene/5172) leads to a depolarizing shift, which would impair synaptic inhibition. ### Therapeutic Potential As [SLC26A4](/details-gene/5172) is a cell-surface transporter, it is a potentially druggable target. Because loss-of-function mutations cause Pendred syndrome, therapeutic **inhibition** is unlikely to be beneficial and would mimic the disease state. However, developing small-molecule **activators or potentiators** of [SLC26A4](/details-gene/5172) could represent a novel therapeutic strategy. Such compounds could potentially be explored for treating conditions characterized by deficient anion transport. For instance, enhancing its bicarbonate transport activity might offer a compensatory mechanism in disorders like cystic fibrosis, where the primary defect lies in a different anion transporter (CFTR). The gene's specific expression pattern could allow for targeted therapies with a reduced risk of widespread, off-target effects.

Genular Protein ID: 2938473908

Symbol: S26A4_HUMAN

Name: Pendrin

UniProtKB Accession Codes:

O43511 B7Z266 O43170

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 10 ChEMBL 1 DNASU 1 DisGeNET 1 DrugBank 1 EMBL 4 EMDB 3 Ensembl 1 ExpressionAtlas 1 GO 19 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 Orphanet 4 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 2 RefSeq 2 Rhea 9 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9398842

Title: Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).

PubMed ID: 9398842

DOI: 10.1038/ng1297-411

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 12853948

Title: The DNA sequence of human chromosome 7.

PubMed ID: 12853948

DOI: 10.1038/nature01782

PubMed ID: 10192399

Title: The Pendred syndrome gene encodes a chloride-iodide transport protein.

PubMed ID: 10192399

DOI: 10.1038/7783

PubMed ID: 10644529

Title: Human pendrin expressed in Xenopus laevis oocytes mediates chloride/formate exchange.

PubMed ID: 10644529

DOI: 10.1152/ajpcell.2000.278.1.c207

PubMed ID: 11274445

Title: Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion.

PubMed ID: 11274445

DOI: 10.1073/pnas.071516798

PubMed ID: 12107249

Title: Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells.

PubMed ID: 12107249

DOI: 10.1210/jcem.87.7.8679

PubMed ID: 15155570

Title: Mechanism of iodide/chloride exchange by pendrin.

PubMed ID: 15155570

DOI: 10.1210/en.2004-0048

PubMed ID: 35601831

Title: Identification of IQGAP1 as a SLC26A4 (Pendrin)-Binding Protein in the Kidney.

PubMed ID: 35601831

DOI: 10.3389/fmolb.2022.874186

PubMed ID: 9618166

Title: Two frequent missense mutations in Pendred syndrome.

PubMed ID: 9618166

DOI: 10.1093/hmg/7.7.1099

PubMed ID: 9618167

Title: Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre).

PubMed ID: 9618167

DOI: 10.1093/hmg/7.7.1105

PubMed ID: 9500541

Title: A mutation in PDS causes non-syndromic recessive deafness.

PubMed ID: 9500541

DOI: 10.1038/ng0398-215

PubMed ID: 10190331

Title: Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.

PubMed ID: 10190331

DOI: 10.1007/s004390050933

PubMed ID: 10602116

Title: Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation.

PubMed ID: 10602116

DOI: 10.1002/(sici)1096-8628(20000103)90:1<38::aid-ajmg8>3.3.co;2-i

PubMed ID: 10718825

Title: A novel mutation in the pendrin gene associated with Pendred's syndrome.

PubMed ID: 10718825

DOI: 10.1046/j.1365-2265.2000.00930.x

PubMed ID: 10878664

Title: Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus.

PubMed ID: 10878664

DOI: 10.1038/sj.ejhg.5200489

PubMed ID: 10700480

Title: Enlarged vestibular aqueduct: a radiological marker of Pendred syndrome, and mutation of the PDS gene.

PubMed ID: 10700480

DOI: 10.1093/qjmed/93.2.99

PubMed ID: 11375792

Title: Clinical and molecular analysis of three Mexican families with Pendred's syndrome.

PubMed ID: 11375792

DOI: 10.1530/eje.0.1440585

PubMed ID: 11317356

Title: Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations.

PubMed ID: 11317356

DOI: 10.1002/humu.1116

PubMed ID: 11748854

Title: Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment.

PubMed ID: 11748854

DOI: 10.1002/humu.1238

PubMed ID: 12112665

Title:

PubMed ID: 12112665

DOI: 10.1002/humu.9043

PubMed ID: 11932316

Title: Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome.

PubMed ID: 11932316

DOI: 10.1210/jcem.87.4.8435

PubMed ID: 11919333

Title: Differential diagnosis between Pendred and pseudo-Pendred syndromes: clinical, radiologic, and molecular studies.

PubMed ID: 11919333

DOI: 10.1203/00006450-200204000-00013

PubMed ID: 12974744

Title: Screening the SLC26A4 gene in probands with deafness and goiter (Pendred syndrome) ascertained from a large group of students of the schools for the deaf in Turkey.

PubMed ID: 12974744

DOI: 10.1034/j.1399-0004.2003.00144.x

PubMed ID: 14508505

Title: Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese.

PubMed ID: 14508505

DOI: 10.1038/sj.ejhg.5201073

PubMed ID: 12788906

Title: Mutations in the PDS gene in German families with Pendred's syndrome: V138F is a founder mutation.

PubMed ID: 12788906

DOI: 10.1210/jc.2002-021334

PubMed ID: 12676893

Title: Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness.

PubMed ID: 12676893

DOI: 10.1136/jmg.40.4.242

PubMed ID: 14679580

Title: Pendred syndrome and DFNB4-mutation screening of SLC26A4 by denaturing high-performance liquid chromatography and the identification of eleven novel mutations.

PubMed ID: 14679580

DOI: 10.1002/ajmg.a.20272

PubMed ID: 15355436

Title: Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity.

PubMed ID: 15355436

DOI: 10.1111/j.1399-0004.2004.00296.x

PubMed ID: 15531480

Title: Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene.

PubMed ID: 15531480

DOI: 10.1210/jc.2004-1013

PubMed ID: 15689455

Title: SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities.

PubMed ID: 15689455

DOI: 10.1136/jmg.2004.024208

PubMed ID: 16684826

Title: Goitrous congenital hypothyroidism and hearing impairment associated with mutations in the TPO and SLC26A4/PDS genes.

PubMed ID: 16684826

DOI: 10.1210/jc.2006-0142

PubMed ID: 17146393

Title: Temporal bone imaging in GJB2 deafness.

PubMed ID: 17146393

DOI: 10.1097/01.mlg.0000244389.68568.a7

PubMed ID: 19204907

Title: Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?

PubMed ID: 19204907

DOI: 10.1002/humu.20884

PubMed ID: 20597900

Title: Spectrum and frequency of SLC26A4 mutations among Czech patients with early hearing loss with and without enlarged vestibular aqueduct (EVA).

PubMed ID: 20597900

DOI: 10.1111/j.1469-1809.2010.00581.x

PubMed ID: 20108392

Title: Novel human pathological mutations. Gene symbol: SLC26A4. Disease: Deafness, non-syndromic, autosomal recessive.

PubMed ID: 20108392

PubMed ID: 24051746

Title: Use of SLC26A4 mutation testing for unilateral enlargement of the vestibular aqueduct.

PubMed ID: 24051746

DOI: 10.1001/jamaoto.2013.4185

PubMed ID: 27535533

Title: Analysis of protein-coding genetic variation in 60,706 humans.

PubMed ID: 27535533

DOI: 10.1038/nature19057

PubMed ID: 28281779

Title: Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or Syndromic Hearing Loss.

PubMed ID: 28281779

DOI: 10.1089/gtmb.2016.0328

Sequence Information:

  • Length: 780
  • Mass: 85723
  • Checksum: 3AEF5D720B155CE0
  • Sequence:
    • MAAPGGRSEP PQLPEYSCSY MVSRPVYSEL AFQQQHERRL QERKTLRESL AKCCSCSRKR 
AFGVLKTLVP ILEWLPKYRV KEWLLSDVIS GVSTGLVATL QGMAYALLAA VPVGYGLYSA 
FFPILTYFIF GTSRHISVGP FPVVSLMVGS VVLSMAPDEH FLVSSSNGTV LNTTMIDTAA 
RDTARVLIAS ALTLLVGIIQ LIFGGLQIGF IVRYLADPLV GGFTTAAAFQ VLVSQLKIVL 
NVSTKNYNGV LSIIYTLVEI FQNIGDTNLA DFTAGLLTIV VCMAVKELND RFRHKIPVPI 
PIEVIVTIIA TAISYGANLE KNYNAGIVKS IPRGFLPPEL PPVSLFSEML AASFSIAVVA 
YAIAVSVGKV YATKYDYTID GNQEFIAFGI SNIFSGFFSC FVATTALSRT AVQESTGGKT 
QVAGIISAAI VMIAILALGK LLEPLQKSVL AAVVIANLKG MFMQLCDIPR LWRQNKIDAV 
IWVFTCIVSI ILGLDLGLLA GLIFGLLTVV LRVQFPSWNG LGSIPSTDIY KSTKNYKNIE 
EPQGVKILRF SSPIFYGNVD GFKKCIKSTV GFDAIRVYNK RLKALRKIQK LIKSGQLRAT 
KNGIISDAVS TNNAFEPDED IEDLEELDIP TKEIEIQVDW NSELPVKVNV PKVPIHSLVL 
DCGAISFLDV VGVRSLRVIV KEFQRIDVNV YFASLQDYVI EKLEQCGFFD DNIRKDTFFL 
TVHDAILYLQ NQVKSQEGQG SILETITLIQ DCKDTLELIE TELTEEELDV QDEAMRTLAS