Details for: EXTL3

Gene ID: 2137

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: EXTL3

Ensembl ID: ENSG00000012232

Description: exostosin like glycosyltransferase 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • Bergmann glial cell CL0000644
    CSI 10.27
    rCSI 14.06%
    PRS 79.66
  • peripheral nervous system neuron CL2000032
    CSI 4.52
    rCSI 6.17%
    PRS 80.83
  • pancreatic D cell CL0000173
    CSI 4.04
    rCSI 3.97%
    PRS 89.37
  • mesothelial cell CL0000077
    CSI 3.71
    rCSI 14.52%
    PRS 68.93
  • cerebellar granule cell CL0001031
    CSI 3.7
    rCSI 5.43%
    PRS 81.79
  • melanocyte CL0000148
    CSI 3.57
    rCSI 2.65%
    PRS 83
  • radial glial cell CL0000681
    CSI 3.56
    rCSI 4.94%
    PRS 86.09
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 3.49
    rCSI 6.16%
    PRS 72.38
  • retinal pigment epithelial cell CL0002586
    CSI 3.48
    rCSI 6.91%
    PRS 83.88
  • Mueller cell CL0000636
    CSI 3.17
    rCSI 7.24%
    PRS 80.51
  • neural crest cell CL0011012
    CSI 3.15
    rCSI 2.49%
    PRS 79.31
  • Kupffer cell CL0000091
    CSI 3.15
    rCSI 7.19%
    PRS 88.64
  • astrocyte of the cerebral cortex CL0002605
    CSI 3.08
    rCSI 6.91%
    PRS 73.58
  • blood vessel endothelial cell CL0000071
    CSI 3.06
    rCSI 6.34%
    PRS 85.52
  • glioblast CL0000030
    CSI 3.04
    rCSI 4.85%
    PRS 79.8
  • retinal bipolar neuron CL0000748
    CSI 2.94
    rCSI 5.51%
    PRS 78.04
  • epithelial cell CL0000066
    CSI 2.94
    rCSI 4.51%
    PRS 76.26
  • inhibitory interneuron CL0000498
    CSI 2.78
    rCSI 6.43%
    PRS 77.68
  • VIP GABAergic cortical interneuron CL4023016
    CSI 2.76
    rCSI 3.3%
    PRS 73.06
  • L6b glutamatergic cortical neuron CL4023038
    CSI 2.73
    rCSI 8.53%
    PRS 74.31
  • interneuron CL0000099
    CSI 2.71
    rCSI 5.44%
    PRS 80.54
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 2.63
    rCSI 3.03%
    PRS 80.33
  • cerebral cortex endothelial cell CL1001602
    CSI 2.62
    rCSI 4.54%
    PRS 81.28
  • choroid plexus epithelial cell CL0000706
    CSI 2.49
    rCSI 4.09%
    PRS 79.46
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.48
    rCSI 3.08%
    PRS 70.71
  • pancreatic A cell CL0000171
    CSI 2.41
    rCSI 2.52%
    PRS 89.9
  • ependymal cell CL0000065
    CSI 2.4
    rCSI 4.87%
    PRS 68.79
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 2.4
    rCSI 3.08%
    PRS 84.17
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 2.39
    rCSI 1.84%
    PRS 90.83
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 2.36
    rCSI 13.91%
    PRS 73.37
  • retinal rod cell CL0000604
    CSI 2.34
    rCSI 4.12%
    PRS 83.17
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 2.27
    rCSI 7.47%
    PRS 75.25
  • hepatic stellate cell CL0000632
    CSI 2.24
    rCSI 8.4%
    PRS 82.06
  • rod bipolar cell CL0000751
    CSI 2.19
    rCSI 3.93%
    PRS 82.11
  • pancreatic acinar cell CL0002064
    CSI 2.14
    rCSI 2.84%
    PRS 91.29
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.01
    rCSI 2.59%
    PRS 74.01
  • cerebral cortex neuron CL0010012
    CSI 1.9
    rCSI 7.76%
    PRS 80.14
  • cardiac endothelial cell CL0010008
    CSI 1.81
    rCSI 7.32%
    PRS 88.15
  • vascular leptomeningeal cell CL4023051
    CSI 1.81
    rCSI 3.17%
    PRS 83.23
  • stem cell CL0000034
    CSI 1.74
    rCSI 1.68%
    PRS 82.83
  • glutamatergic neuron CL0000679
    CSI 1.59
    rCSI 3.27%
    PRS 75.47
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 1.56
    rCSI 5.89%
    PRS 73.18
  • cardiac muscle cell CL0000746
    CSI 1.54
    rCSI 2.2%
    PRS 79.09
  • retinal ganglion cell CL0000740
    CSI 1.47
    rCSI 3.24%
    PRS 75.8
  • macroglial cell CL0000126
    CSI 1.45
    rCSI 3.73%
    PRS 83.83
  • epicardial adipocyte CL1000309
    CSI 1.42
    rCSI 4.62%
    PRS 84.86
  • direct pathway medium spiny neuron CL4023026
    CSI 1.42
    rCSI 33.95%
    PRS 70.51
  • extravillous trophoblast CL0008036
    CSI 1.42
    rCSI 1.75%
    PRS 86.04
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.34
    rCSI 2.16%
    PRS 74
  • GABAergic neuron CL0000617
    CSI 1.34
    rCSI 4.49%
    PRS 73.25
  • regular atrial cardiac myocyte CL0002129
    CSI 1.32
    rCSI 4.25%
    PRS 84.39
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 1.31
    rCSI 3.12%
    PRS 76.32
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.29
    rCSI 31.23%
    PRS 70.96
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.22
    rCSI 2.04%
    PRS 72.91
  • central nervous system neuron CL2000029
    CSI 1.11
    rCSI 8.15%
    PRS 77.74
  • basket cell CL0000118
    CSI 1.07
    rCSI 6.69%
    PRS 66.95
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.04
    rCSI 2.53%
    PRS 70.66
  • dopaminergic neuron CL0000700
    CSI 0.76
    rCSI 4.31%
    PRS 76.1
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 0.68
    rCSI 2.11%
    PRS 76.36
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.63
    rCSI 2.25%
    PRS 70.88
  • regular ventricular cardiac myocyte CL0002131
    CSI 0.52
    rCSI 3.24%
    PRS 80.8
  • medium spiny neuron CL1001474
    CSI 0.2
    rCSI 1.72%
    PRS 78.4

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)

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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 [EXTL3](/details-gene/2137), or Exostosin Like Glycosyltransferase 3, is a protein-coding gene located on chromosome 8p21.1. It encodes a type II transmembrane glycosyltransferase, specifically a glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, which is crucial for the biosynthesis of heparan sulfate (HS) proteoglycans. Functioning primarily within the endoplasmic reticulum and Golgi apparatus, [EXTL3](/details-gene/2137) is essential for proper protein glycosylation and the synthesis of HS chains, which are vital for cell-cell signaling, morphogenesis, and development [Link](https://doi.org/10.1073/pnas.131188498). Its expression profile indicates a particularly significant role in the central nervous system, with its highest significance observed in [Bergmann glial cell](/details-cell/CL0000644). Mutations in this gene are known to cause a rare autosomal recessive neuro-immuno-skeletal dysplasia syndrome, underscoring its critical, multi-systemic functions [Link](https://doi.org/10.1016/j.ajhg.2017.01.013), [Link](https://doi.org/10.1084/jem.20161525). ## Cellular Roles and Expression Landscape The expression landscape of [EXTL3](/details-gene/2137) highlights its prominent role in the development and maintenance of the nervous system. **Overall**, the gene shows its most profound significance in [Bergmann glial cell](/details-cell/CL0000644) (CSI: 10.27), a specialized astrocyte of the cerebellum essential for guiding neuronal migration and supporting synaptic function. This is complemented by high significance scores in a broad range of other neural and glial cell types, including [peripheral nervous system neuron](/details-cell/CL2000032), [cerebellar granule cell](/details-cell/CL0001031), [radial glial cell](/details-cell/CL0000681), [astrocyte of the cerebral cortex](/details-cell/CL0002605), and [Mueller cell](/details-cell/CL0000636) of the retina. This widespread expression across diverse neural lineages suggests that [EXTL3](/details-gene/2137)-mediated heparan sulfate synthesis is a fundamental process for neuronal development, connectivity, and glial support. Beyond the nervous system, [EXTL3](/details-gene/2137) is also significant in other specialized cells. Its expression in [pancreatic D cell](/details-cell/CL0000173) suggests a potential role in endocrine function and islet cell biology. Furthermore, its notable presence in [melanocyte](/details-cell/CL0000148), [mesothelial cell](/details-cell/CL0000077), and the liver-resident macrophage, the [Kupffer cell](/details-cell/CL0000091), points towards broader functions in tissue homeostasis, barrier integrity, and innate immunity. ## Pathways and Molecular Function The primary molecular function of [EXTL3](/details-gene/2137) is its enzymatic activity as a glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase ([GO:0001888](https://www.ebi.ac.uk/QuickGO/term/GO:0001888)), a key step in the heparan sulfate proteoglycan biosynthetic process ([GO:0015012](https://www.ebi.ac.uk/QuickGO/term/GO:0015012)). This function is integral to protein glycosylation ([GO:0006486](https://www.ebi.ac.uk/QuickGO/term/GO:0006486)) and occurs within the endoplasmic reticulum ([GO:0005783](https://www.ebi.ac.uk/QuickGO/term/GO:0005783)) and Golgi apparatus ([GO:0005794](https://www.ebi.ac.uk/QuickGO/term/GO:0005794)). Functionally, [EXTL3](/details-gene/2137) is implicated in pathways that extend beyond glycosylation. It is annotated with roles in the negative regulation of inflammatory responses ([GO:0050728](https://www.ebi.ac.uk/QuickGO/term/GO:0050728)) and cytokine production ([GO:1900016](https://www.ebi.ac.uk/QuickGO/term/GO:1900016)), which aligns with the immune deficiency observed in patients with [EXTL3](/details-gene/2137) mutations [Link](https://doi.org/10.1084/jem.20161525). It also acts as a receptor for REG3 family proteins, which can activate the RAS-RAF-MEK-ERK signaling pathway to promote metaplasia in the pancreas [Link](https://doi.org/10.1038/s42003-021-02193-z). Furthermore, its involvement in the Unfolded Protein Response (UPR) ([R-HSA-381119](https://reactome.org/content/detail/R-HSA-381119)) is consistent with its role as an ER-resident enzyme managing protein modification and cellular stress. ## Research Directions The diverse phenotypic consequences of [EXTL3](/details-gene/2137) mutations, spanning neurological, skeletal, and immune systems, highlight its fundamental importance. The gene's exceptionally high significance in specific neural cell types, combined with its established role in disease, provides fertile ground for further investigation. **Proposed Hypotheses:** 1. Given its paramount significance in [Bergmann glial cell](/details-cell/CL0000644), it is hypothesized that [EXTL3](/details-gene/2137) is indispensable for cerebellar development and function. Loss of [EXTL3](/details-gene/2137) in these cells may disrupt the synthesis of specific heparan sulfate proteoglycans required for Purkinje cell dendritic arborization and synaptic maintenance, directly contributing to the neurological deficits seen in EXTL3-related dysplasia. 2. The established interaction between [EXTL3](/details-gene/2137) and REG3 proteins, which drives signaling in pancreatic tissue [Link](https://doi.org/10.1038/s42003-021-02193-z), combined with the gene's expression in [pancreatic D cell](/details-cell/CL0000173), suggests a novel role in islet cell regulation. It is hypothesized that the REG3-[EXTL3](/details-gene/2137) axis participates in paracrine signaling within pancreatic islets, potentially modulating somatostatin secretion from D cells and influencing overall glucose homeostasis. **Experimental Approach:** To test the first hypothesis, a conditional knockout mouse model could be generated using a Cre-Lox system to specifically delete *Extl3* in Bergmann glia (e.g., using a Gdf10-Cre driver). The resulting phenotype could be assessed through multiple approaches: * **Histological Analysis:** Immunofluorescence staining of cerebellar sections for Purkinje cell markers (e.g., Calbindin) and synaptic markers to quantify dendritic complexity and synapse density. * **Electrophysiology:** Patch-clamp recordings from Purkinje cells in cerebellar slices to measure alterations in excitatory and inhibitory synaptic transmission. * **Behavioral Testing:** A battery of motor coordination tests (e.g., rotarod, beam walking) to determine if the cellular defects translate to an ataxic phenotype, mirroring the neurological symptoms in patients. **Therapeutic Potential:** Because EXTL3-related dysplasia is a loss-of-function, autosomal recessive disorder, therapeutic strategies would logically focus on **activation** or restoration of function rather than inhibition. The primary challenge is targeting an intracellular enzyme within the ER/Golgi complex. For this monogenic disorder, gene therapy represents a potential long-term strategy to restore [EXTL3](/details-gene/2137) expression in affected tissues. Conversely, in pathological contexts such as pancreatitis or certain cancers where the REG3-[EXTL3](/details-gene/2137) axis promotes aberrant cell proliferation [Link](https://doi.org/10.1038/s42003-021-02193-z), [EXTL3](/details-gene/2137) could become a target for **inhibition**, potentially using small molecules or biologics to disrupt its interaction with ligands or its enzymatic activity.

Genular Protein ID: 4044572015

Symbol: EXTL3_HUMAN

Name: Glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase

UniProtKB Accession Codes:

O43909 D3DST8 O00225 Q53XT3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CAZy 2 CCDS 1 CTD 1 ChEBI 18 ChiTaRS 1 DNASU 1 DisGeNET 1 EC 1 EMBL 12 EMDB 2 Ensembl 5 ExpressionAtlas 1 GO 19 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 4 PDBsum 4 PIR 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 1 RefSeq 2 Rhea 3 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9479495

Title: Identification of a third EXT-like gene (EXTL3) belonging to the EXT gene family.

PubMed ID: 9479495

DOI: 10.1006/geno.1997.5101

PubMed ID: 9473480

Title: Structure, chromosomal location, and expression profile of EXTR1 and EXTR2, new members of the multiple exostoses gene family.

PubMed ID: 9473480

DOI: 10.1006/bbrc.1997.8062

PubMed ID: 9628581

Title: Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.

PubMed ID: 9628581

DOI: 10.1093/dnares/5.1.31

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: 10639137

Title: The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate.

PubMed ID: 10639137

DOI: 10.1073/pnas.97.2.668

PubMed ID: 11390981

Title: Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha 1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis.

PubMed ID: 11390981

DOI: 10.1073/pnas.131188498

PubMed ID: 19158046

Title: Discovery of a human peptide sequence signaling islet neogenesis.

PubMed ID: 19158046

DOI: 10.4158/ep.14.9.1075

PubMed ID: 22727489

Title: The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury.

PubMed ID: 22727489

DOI: 10.1016/j.immuni.2012.04.010

PubMed ID: 27830702

Title: Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes.

PubMed ID: 27830702

DOI: 10.1038/ncomms13393

PubMed ID: 28132690

Title: Mutations in EXTL3 cause neuro-immuno-skeletal dysplasia syndrome.

PubMed ID: 28132690

DOI: 10.1016/j.ajhg.2017.01.013

PubMed ID: 28148688

Title: EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.

PubMed ID: 28148688

DOI: 10.1084/jem.20161525

PubMed ID: 29346724

Title: Structural and Biophysical Characterization of Human EXTL3: Domain Organization, Glycosylation, and Solution Structure.

PubMed ID: 29346724

DOI: 10.1021/acs.biochem.7b00557

PubMed ID: 34099862

Title: REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway.

PubMed ID: 34099862

DOI: 10.1038/s42003-021-02193-z

PubMed ID: 35676258

Title: The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis.

PubMed ID: 35676258

DOI: 10.1038/s41467-022-31048-2

PubMed ID: 28397838

Title: Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.

PubMed ID: 28397838

DOI: 10.1038/mp.2017.60

Sequence Information:

  • Length: 919
  • Mass: 104749
  • Checksum: 200ADD4DAB4A39FD
  • Sequence:
    • MTGYTMLRNG GAGNGGQTCM LRWSNRIRLT WLSFTLFVIL VFFPLIAHYY LTTLDEADEA 
GKRIFGPRVG NELCEVKHVL DLCRIRESVS EELLQLEAKR QELNSEIAKL NLKIEACKKS 
IENAKQDLLQ LKNVISQTEH SYKELMAQNQ PKLSLPIRLL PEKDDAGLPP PKATRGCRLH 
NCFDYSRCPL TSGFPVYVYD SDQFVFGSYL DPLVKQAFQA TARANVYVTE NADIACLYVI 
LVGEMQEPVV LRPAELEKQL YSLPHWRTDG HNHVIINLSR KSDTQNLLYN VSTGRAMVAQ 
STFYTVQYRP GFDLVVSPLV HAMSEPNFME IPPQVPVKRK YLFTFQGEKI ESLRSSLQEA 
RSFEEEMEGD PPADYDDRII ATLKAVQDSK LDQVLVEFTC KNQPKPSLPT EWALCGERED 
RLELLKLSTF ALIITPGDPR LVISSGCATR LFEALEVGAV PVVLGEQVQL PYQDMLQWNE 
AALVVPKPRV TEVHFLLRSL SDSDLLAMRR QGRFLWETYF STADSIFNTV LAMIRTRIQI 
PAAPIREEAA AEIPHRSGKA AGTDPNMADN GDLDLGPVET EPPYASPRYL RNFTLTVTDF 
YRSWNCAPGP FHLFPHTPFD PVLPSEAKFL GSGTGFRPIG GGAGGSGKEF QAALGGNVPR 
EQFTVVMLTY EREEVLMNSL ERLNGLPYLN KVVVVWNSPK LPSEDLLWPD IGVPIMVVRT 
EKNSLNNRFL PWNEIETEAI LSIDDDAHLR HDEIMFGFRV WREARDRIVG FPGRYHAWDI 
PHQSWLYNSN YSCELSMVLT GAAFFHKYYA YLYSYVMPQA IRDMVDEYIN CEDIAMNFLV 
SHITRKPPIK VTSRWTFRCP GCPQALSHDD SHFHERHKCI NFFVKVYGYM PLLYTQFRVD 
SVLFKTRLPH DKTKCFKFI