Details for: SLC4A11

Gene ID: 83959

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: SLC4A11

Ensembl ID: ENSG00000088836

Description: solute carrier family 4 member 11

Cell Significance Landscape

Associated with

Significant Cells

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

  • parietal epithelial cell CL1000452
    CSI 6.79
    rCSI 18.15%
    PRS 92.77
  • duct epithelial cell CL0000068
    CSI 5.92
    rCSI 8.66%
    PRS 97.39
  • secretory cell CL0000151
    CSI 4.18
    rCSI 4.36%
    PRS 94.83
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 4.04
    rCSI 10.44%
    PRS 94.17
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 3.87
    rCSI 5.49%
    PRS 94.44
  • ionocyte CL0005006
    CSI 3.44
    rCSI 3.69%
    PRS 96.2
  • pulmonary ionocyte CL0017000
    CSI 3.4
    rCSI 4.14%
    PRS 97.08
  • nasal mucosa goblet cell CL0002480
    CSI 3.37
    rCSI 3.91%
    PRS 95.04
  • squamous epithelial cell CL0000076
    CSI 3.15
    rCSI 7.48%
    PRS 92.25
  • renal interstitial pericyte CL1001318
    CSI 2.82
    rCSI 7.78%
    PRS 94.65
  • ciliated cell CL0000064
    CSI 2.73
    rCSI 4.42%
    PRS 90.69
  • club cell CL0000158
    CSI 2.32
    rCSI 3.39%
    PRS 93.17
  • acinar cell CL0000622
    CSI 2.26
    rCSI 3.31%
    PRS 97.8
  • multi-ciliated epithelial cell CL0005012
    CSI 2.23
    rCSI 2.22%
    PRS 91.78
  • tracheal goblet cell CL1000329
    CSI 1.56
    rCSI 3.4%
    PRS 96.09
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 1
    rCSI 2.29%
    PRS 90.08

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.

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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)

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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 [SLC4A11](/details-gene/83959) is a protein-coding gene on chromosome 20 that encodes Solute Carrier Family 4 Member 11, a multi-functional transmembrane transporter. Functional annotations and experimental evidence characterize it as a transporter of bicarbonate, borate, sodium, protons, and water. **Overall**, its expression is most significant in specialized epithelial cell types, including those in the kidney and respiratory tract, such as [parietal epithelial cell](/details-cell/CL1000452) and [duct epithelial cell](/details-cell/CL0000068), suggesting a crucial role in maintaining fluid and ion homeostasis across biological barriers. Clinically, loss-of-function mutations in [SLC4A11](/details-gene/83959) are directly implicated in severe genetic disorders of the eye, including congenital hereditary endothelial dystrophy ([217400](https://omim.org/entry/217400)) and Harboyan syndrome ([217700](https://omim.org/entry/217700)). ## Cellular Roles and Expression Landscape The expression profile of [SLC4A11](/details-gene/83959) highlights its specialized function in cells dedicated to fluid regulation and secretion. **Overall**, the gene shows the highest significance in epithelial lineages responsible for creating and maintaining physiological barriers. Its most prominent expression is in renal epithelial cells, with top significance scores in [parietal epithelial cell](/details-cell/CL1000452) (CSI: 6.79) of the Bowman's capsule, as well as epithelial cells of the [kidney loop of Henle thin ascending limb](/details-cell/CL1001107) and [descending limb](/details-cell/CL1001111). This pattern is consistent with a vital role in water and solute reabsorption within the kidney. A similar theme of barrier function is evident in other tissues. High significance is observed in specialized cells of the respiratory tract, including [pulmonary ionocyte](/details-cell/CL0017000), [nasal mucosa goblet cell](/details-cell/CL0002480), and [ciliated cell](/details-cell/CL0000064). This suggests its involvement in regulating the composition of airway surface liquid. The gene's importance in diverse secretory and transport-focused cell types, such as [duct epithelial cell](/details-cell/CL0000068) and [secretory cell](/details-cell/CL0000151), reinforces its identity as a fundamental component of epithelial transport machinery across multiple organ systems. While not explicitly listed in the provided data, multiple studies confirm its critical expression in corneal endothelial cells, which is central to its known pathology ([Link](https://doi.org/10.1038/s41598-019-46094-y)). ## Pathways and Molecular Function The molecular functions attributed to [SLC4A11](/details-gene/83959) align with its expression pattern in transport-specialized cells. Localized primarily to the [plasma membrane](/details-cell/GO:0005886), including both [apical](/details-cell/GO:0016324) and [basolateral](/details-cell/GO:0016323) domains, it operates as a versatile transporter. Gene Ontology annotations and functional studies confirm its activity in [bicarbonate transport](/details-cell/GO:0015701) ([Link](https://doi.org/10.1006/bbrc.2001.4692)), electrogenic Na+-coupled [borate transport](/details-cell/GO:0046713) ([Link](https://doi.org/10.1016/j.molcel.2004.09.030)), and transmembrane [water transport](/details-cell/GO:0006833) ([Link](https://doi.org/10.1093/hmg/ddt307)). These diverse transport capabilities enable [SLC4A11](/details-gene/83959) to play a central role in maintaining cellular pH, ion gradients, and osmotic balance. Beyond its transport functions, [SLC4A11](/details-gene/83959) is implicated in the [cellular response to oxidative stress](/details-cell/GO:0034599). Research indicates that its depletion in human corneal endothelial cells impairs NRF2-mediated antioxidant signaling, leading to an increase in reactive oxygen species ([Link](https://doi.org/10.1038/s41598-017-03654-4)). This suggests that [SLC4A11](/details-gene/83959) not only manages physical transport but also contributes to cellular defense mechanisms, a function that may be particularly important in metabolically active tissues like the corneal endothelium. ## Research Directions The well-established link between [SLC4A11](/details-gene/83959) mutations and corneal dystrophies provides a clear focus for future research into its pathophysiology. The gene's dual roles in fluid transport and oxidative stress response suggest multiple mechanisms by which its dysfunction could lead to disease. ### Proposed Hypotheses: 1. **Impaired Oxidative Stress Response:** Given the role of [SLC4A11](/details-gene/83959) in NRF2 signaling ([Link](https://doi.org/10.1038/s41598-017-03654-4)), it is hypothesized that disease-causing mutations disrupt its interaction with the antioxidant machinery. This would render corneal endothelial cells, which are under constant metabolic and UV-induced stress, highly susceptible to oxidative damage, leading to apoptosis and loss of endothelial cell density characteristic of Fuchs' and congenital endothelial dystrophies. 2. **Defective Water Flux and Osmotic Regulation:** The primary function of the corneal endothelium is to pump water out of the corneal stroma to maintain transparency. We hypothesize that pathogenic mutations in [SLC4A11](/details-gene/83959) directly compromise its function as a water and ion channel ([Link](https://doi.org/10.1093/hmg/ddt307)), leading to impaired fluid transport. This defect would result in chronic corneal edema, stromal thickening, and the eventual loss of visual acuity observed in patients. ### Key Experimental Approach: To test the hypothesis regarding defective water flux (Hypothesis 2), one could use an *in vitro* assay with human corneal endothelial cells (HCECs). HCECs would be engineered using CRISPR-Cas9 to harbor specific pathogenic mutations found in patients with CHED2 ([217400](https://omim.org/entry/217400)). These mutant cell lines, alongside wild-type controls, would be grown on permeable supports to form a monolayer. The rate of fluid transport across the monolayer could then be measured directly in response to an osmotic challenge. Furthermore, the specific water and ion permeability of the cells could be quantified using biophysical techniques like calcein quenching assays to assess water flux, thereby directly linking specific mutations to a measurable defect in the protein's transport function. ### Therapeutic Potential: Since congenital hereditary endothelial dystrophy is a loss-of-function monogenic disorder, [SLC4A11](/details-gene/83959) is not a target for inhibition. Instead, therapeutic strategies should aim to restore its function. Gene therapy represents the most direct approach, potentially using AAV vectors to deliver a functional copy of the [SLC4A11](/details-gene/83959) gene to the corneal endothelium via intracameral injection. Another potential avenue is the development of pharmacological chaperones or potentiators, which are small molecules designed to correct the misfolding of mutant proteins or enhance the residual transport activity of the defective channels, offering a non-surgical therapeutic option for patients.

Genular Protein ID: 3844734449

Symbol: S4A11_HUMAN

Name: Solute carrier family 4 member 11

UniProtKB Accession Codes:

Q8NBS3 B4DKC8 B4DKX9 G3V1M3 Q2TB62 Q2TB63 Q9BXF4 Q9NTW9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CTD 1 ChEBI 2 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 8 EMDB 4 Ensembl 3 ExpressionAtlas 1 GO 27 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 7 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 3 OrthoDB 1 PANTHER 2 PDB 4 PDBsum 4 PRINTS 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 RefSeq 8 Rhea 2 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 11302728

Title: Human BTR1, a new bicarbonate transporter superfamily member and human AE4 from kidney.

PubMed ID: 11302728

DOI: 10.1006/bbrc.2001.4692

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 11780052

Title: The DNA sequence and comparative analysis of human chromosome 20.

PubMed ID: 11780052

DOI: 10.1038/414865a

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15525507

Title: NaBC1 is a ubiquitous electrogenic Na+-coupled borate transporter essential for cellular boron homeostasis and cell growth and proliferation.

PubMed ID: 15525507

DOI: 10.1016/j.molcel.2004.09.030

PubMed ID: 21288032

Title: A biochemical framework for SLC4A11, the plasma membrane protein defective in corneal dystrophies.

PubMed ID: 21288032

DOI: 10.1021/bi101887z

PubMed ID: 23813972

Title: Transmembrane water-flux through SLC4A11: a route defective in genetic corneal diseases.

PubMed ID: 23813972

DOI: 10.1093/hmg/ddt307

PubMed ID: 27581649

Title: Multifunctional ion transport properties of human SLC4A11: comparison of the SLC4A11-B and SLC4A11-C variants.

PubMed ID: 27581649

DOI: 10.1152/ajpcell.00233.2016

PubMed ID: 28642546

Title: SLC4A11 depletion impairs NRF2 mediated antioxidant signaling and increases reactive oxygen species in human corneal endothelial cells during oxidative stress.

PubMed ID: 28642546

DOI: 10.1038/s41598-017-03654-4

PubMed ID: 31273259

Title: Human Corneal Expression of SLC4A11, a Gene Mutated in Endothelial Corneal Dystrophies.

PubMed ID: 31273259

DOI: 10.1038/s41598-019-46094-y

PubMed ID: 16767101

Title: Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2).

PubMed ID: 16767101

DOI: 10.1038/ng1824

PubMed ID: 17397048

Title: Novel SLC4A11 mutations in patients with recessive congenital hereditary endothelial dystrophy (CHED2). Mutation in brief #958. Online.

PubMed ID: 17397048

DOI: 10.1002/humu.9487

PubMed ID: 16825429

Title: Autosomal recessive corneal endothelial dystrophy (CHED2) is associated with mutations in SLC4A11.

PubMed ID: 16825429

DOI: 10.1136/jmg.2006.044644

PubMed ID: 17220209

Title: Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non-syndromic corneal endothelial dystrophy.

PubMed ID: 17220209

DOI: 10.1136/jmg.2006.046904

PubMed ID: 17679935

Title: Mutational spectrum of the SLC4A11 gene in autosomal recessive congenital hereditary endothelial dystrophy.

PubMed ID: 17679935

PubMed ID: 18474783

Title: Identification of mutations in the SLC4A11 gene in patients with recessive congenital hereditary endothelial dystrophy.

PubMed ID: 18474783

DOI: 10.1001/archopht.126.5.700

PubMed ID: 18024964

Title: SLC4A11 mutations in Fuchs endothelial corneal dystrophy.

PubMed ID: 18024964

DOI: 10.1093/hmg/ddm337

PubMed ID: 19369245

Title: Mutational spectrum of SLC4A11 in autosomal recessive CHED in Saudi Arabia.

PubMed ID: 19369245

DOI: 10.1167/iovs.08-3006

PubMed ID: 20108384

Title: Novel human pathological mutations. Gene symbol: SLC4A11. Disease: Corneal endothelial dystrophy 2.

PubMed ID: 20108384

PubMed ID: 20848555

Title: Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophya.

PubMed ID: 20848555

DOI: 10.1002/humu.21356

PubMed ID: 20185830

Title: SLC4A11 prevents osmotic imbalance leading to corneal endothelial dystrophy, deafness, and polyuria.

PubMed ID: 20185830

DOI: 10.1074/jbc.m109.094680

PubMed ID: 21203343

Title: Congenital hereditary endothelial dystrophy - mutation analysis of SLC4A11 and genotype-phenotype correlation in a North Indian patient cohort.

PubMed ID: 21203343

PubMed ID: 22072594

Title: Oligomerization of SLC4A11 protein and the severity of FECD and CHED2 corneal dystrophies caused by SLC4A11 mutations.

PubMed ID: 22072594

DOI: 10.1002/humu.21655

PubMed ID: 25007886

Title: Biosynthetic and functional defects in newly identified SLC4A11 mutants and absence of COL8A2 mutations in Fuchs endothelial corneal dystrophy.

PubMed ID: 25007886

DOI: 10.1038/jhg.2014.55

PubMed ID: 26286922

Title: Missense mutation in SLC4A11 in two Pakistani families affected with congenital hereditary endothelial dystrophy (CHED2).

PubMed ID: 26286922

DOI: 10.1111/cxo.12276

Sequence Information:

  • Length: 875
  • Mass: 98181
  • Checksum: 6BEDDC9939BADF10
  • Sequence:
    • MAAATRRVFH LQPCENSPTM SQNGYFEDSS YYKCDTDDTF EAREEILGDE AFDTANSSIV 
SGESIRFFVN VNLEMQATNT ENEATSGGCV LLHTSRKYLK LKNFKEEIRA HRDLDGFLAQ 
ASIVLNETAT SLDNVLRTML RRFARDPDNN EPNCNLDLLM AMLFTDAGAP MRGKVHLLSD 
TIQGVTATVT GVRYQQSWLC IICTMKALQK RHVCISRLVR PQNWGENSCE VRFVILVLAP 
PKMKSTKTAM EVARTFATMF SDIAFRQKLL ETRTEEEFKE ALVHQRQLLT MVSHGPVAPR 
TKERSTVSLP AHRHPEPPKC KDFVPFGKGI REDIARRFPL YPLDFTDGII GKNKAVGKYI 
TTTLFLYFAC LLPTIAFGSL NDENTDGAID VQKTIAGQSI GGLLYALFSG QPLVILLTTA 
PLALYIQVIR VICDDYDLDF NSFYAWTGLW NSFFLALYAF FNLSLVMSLF KRSTEEIIAL 
FISITFVLDA VKGTVKIFWK YYYGHYLDDY HTKRTSSLVS LSGLGASLNA SLHTALNASF 
LASPTELPSA THSGQATAVL SLLIMLGTLW LGYTLYQFKK SPYLHPCVRE ILSDCALPIA 
VLAFSLISSH GFREIEMSKF RYNPSESPFA MAQIQSLSLR AVSGAMGLGF LLSMLFFIEQ 
NLVAALVNAP ENRLVKGTAY HWDLLLLAII NTGLSLFGLP WIHAAYPHSP LHVRALALVE 
ERVENGHIYD TIVNVKETRL TSLGASVLVG LSLLLLPVPL QWIPKPVLYG LFLYIALTSL 
DGNQLVQRVA LLLKEQTAYP PTHYIRRVPQ RKIHYFTGLQ VLQLLLLCAF GMSSLPYMKM 
IFPLIMIAMI PIRYILLPRI IEAKYLDVMD AEHRP