Details for: NDST4

Gene ID: 64579

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: NDST4

Ensembl ID: ENSG00000138653

Description: N-deacetylase and N-sulfotransferase 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • sncg GABAergic cortical interneuron CL4023015
    CSI 23.52
    rCSI 37.83%
    PRS 90.21
  • sst GABAergic cortical interneuron CL4023017
    CSI 11.3
    rCSI 14.57%
    PRS 90.42
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 7.89
    rCSI 13.25%
    PRS 89.7
  • glial cell CL0000125
    CSI 6.46
    rCSI 24.59%
    PRS 92.25
  • radial glial cell CL0000681
    CSI 6.1
    rCSI 8.47%
    PRS 95.67
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 5.49
    rCSI 6.34%
    PRS 91.61
  • central nervous system neuron CL2000029
    CSI 5.26
    rCSI 38.64%
    PRS 91.8
  • interneuron CL0000099
    CSI 4.75
    rCSI 9.54%
    PRS 93.52
  • neural progenitor cell CL0011020
    CSI 4.63
    rCSI 20.35%
    PRS 88.61
  • GABAergic amacrine cell CL4030027
    CSI 4.57
    rCSI 15.67%
    PRS 87.93
  • inhibitory interneuron CL0000498
    CSI 4.32
    rCSI 9.96%
    PRS 91.12
  • GABAergic neuron CL0000617
    CSI 3.74
    rCSI 12.54%
    PRS 87.7
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 3.47
    rCSI 4.31%
    PRS 88.01
  • VIP GABAergic cortical interneuron CL4023016
    CSI 3.36
    rCSI 4.02%
    PRS 89.67
  • amacrine cell CL0000561
    CSI 3.24
    rCSI 9.39%
    PRS 91.22
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 2.02
    rCSI 6.31%
    PRS 91.51
  • cerebellar neuron CL1001611
    CSI 1.79
    rCSI 15.72%
    PRS 88.25
  • dopaminergic neuron CL0000700
    CSI 1.49
    rCSI 8.43%
    PRS 89.64
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.41
    rCSI 2.49%
    PRS 89.27
  • retinal ganglion cell CL0000740
    CSI 1.23
    rCSI 2.71%
    PRS 90.28
  • neuroplacodal cell CL0000032
    CSI 0.91
    rCSI 8.43%
    PRS 92.46

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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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 N-deacetylase and N-sulfotransferase 4 ([NDST4](/details-gene/64579)) is a bifunctional enzyme that plays a key role in the biosynthesis of heparan sulfate and heparin, crucial components of the extracellular matrix and cell surface. It catalyzes the N-deacetylation and subsequent N-sulfation of glucosamine residues within developing glycosaminoglycan chains. This modification process occurs within the [Golgi apparatus](/details-cell/GO:0005794). Expression data strongly indicate that [NDST4](/details-gene/64579) is a highly specific marker within the central nervous system, showing pronounced significance in various subtypes of inhibitory GABAergic interneurons and glial cells, suggesting a specialized role in neural development and function. ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [NDST4](/details-gene/64579) demonstrates a highly specialized function within the central nervous system. The gene exhibits its highest significance in specific subtypes of inhibitory neurons, establishing it as a key marker for [sncg GABAergic cortical interneuron](/details-cell/CL4023015) (CSI: 23.52), [sst GABAergic cortical interneuron](/details-cell/CL4023017) (CSI: 11.30), and [lamp5 GABAergic cortical interneuron](/details-cell/CL4023011) (CSI: 7.89). Its importance extends across a range of related cell types, including general [interneuron](/details-cell/CL0000099)s, [GABAergic neuron](/details-cell/CL0000617)s, and [amacrine cell](/details-cell/CL0000561)s. In addition to mature neurons, [NDST4](/details-gene/64579) is also significant in progenitor and support cells, including [glial cell](/details-cell/CL0000125)s, [radial glial cell](/details-cell/CL0000681)s, and [neural progenitor cell](/details-cell/CL0011020)s. This specific expression pattern suggests that the particular heparan sulfate modifications catalyzed by [NDST4](/details-gene/64579) are not broadly required but are instead crucial for the development, connectivity, or functional maintenance of these specific neural and glial populations. ## Pathways and Molecular Function The molecular activities of [NDST4](/details-gene/64579) are central to glycosaminoglycan biosynthesis. Functional annotations confirm its dual role, possessing both [deacetylase activity](/details-cell/GO:0019213) and specifically '[heparan sulfate]-glucosamine n-sulfotransferase activity' ([GO:0015016](https://www.ebi.ac.uk/QuickGO/term/GO:0015016)), as detailed in foundational studies [[Link](https://doi.org/10.1074/jbc.m009606200)]. These enzymatic steps are integral to the 'Heparan sulfate proteoglycan biosynthetic process' ([GO:0015014](https://www.ebi.ac.uk/QuickGO/term/GO:0015014)) and the related 'Heparin biosynthetic process' ([GO:0030210](https://www.ebi.ac.uk/QuickGO/term/GO:0030210)). Reactome pathway analysis situates [NDST4](/details-gene/64579) within the broader framework of '[Metabolism of carbohydrates](/details-cell/R-HSA-71387)', specifically contributing to '[Glycosaminoglycan metabolism](/details-cell/R-HSA-1630316)' and '[Hs-gag biosynthesis](/details-cell/R-HSA-2022928)'. The localization of this activity to the [Golgi membrane](/details-cell/GO:0000139) is consistent with its role in modifying proteoglycans as they are processed for transport to the cell surface or for secretion. In the nervous system, the resulting heparan sulfate structures are critical for regulating axon guidance, synapse formation, and the signaling of various growth factors, providing a direct link between the enzymatic function of [NDST4](/details-gene/64579) and its cellular expression profile. ## Research Directions The highly specific expression of [NDST4](/details-gene/64579) within discrete neuronal populations suggests that its function is not redundant with other NDST isoforms and is likely tailored to the unique requirements of these cells. This specificity warrants further investigation into its precise roles in neural circuit function and its potential involvement in neurological disease. **Proposed Hypotheses:** 1. The unique sulfation patterns generated by [NDST4](/details-gene/64579) on heparan sulfate proteoglycans of cortical interneurons are necessary for creating specific binding sites for morphogens or neurotrophic factors (e.g., Slit, Netrin, or FGFs) that govern synaptic targeting and maintenance of inhibitory circuits. 2. Loss-of-function mutations or dysregulated expression of [NDST4](/details-gene/64579) may contribute to neurodevelopmental disorders or epilepsy by disrupting the excitatory/inhibitory balance in the brain, stemming from impaired interneuron migration, synaptogenesis, or function. **Experimental Approach:** To test the first hypothesis, a conditional knockout (cKO) mouse model could be created using the Cre-LoxP system, crossing a floxed-[NDST4](/details-gene/64579) allele with a Cre driver line specific to a top-expressing cell type, such as Sst-Cre or Pvalb-Cre. Brains from the resulting cKO mice could be analyzed using a combination of techniques. Immunohistochemistry and advanced microscopy could be used to assess interneuron morphology, dendritic arborization, and synaptic density. Electrophysiological recordings from cortical slices would reveal deficits in synaptic transmission and plasticity. Finally, mass spectrometry-based glycomics on isolated proteoglycans would directly identify the specific alterations in heparan sulfate sulfation patterns resulting from the loss of [NDST4](/details-gene/64579). **Therapeutic Potential:** As an intracellular enzyme located in the Golgi, [NDST4](/details-gene/64579) is a challenging direct therapeutic target. However, understanding its function could open new avenues. If specific heparan sulfate structures generated by [NDST4](/details-gene/64579) are found to be deficient in certain neurological disorders, therapeutic strategies could focus on restoring this function downstream. This might involve the development of glycan mimetics or engineered proteins that replicate the binding properties of the [NDST4](/details-gene/64579)-dependent heparan sulfate chains, thereby restoring crucial cell-cell or cell-matrix interactions. Such an approach would target the pathological consequence of the enzyme's deficiency rather than the enzyme itself.

Genular Protein ID: 3747547240

Symbol: NDST4_HUMAN

Name: Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4

UniProtKB Accession Codes:

Q9H3R1 Q2KHM8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 8 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 4 EMBL 6 Ensembl 3 GO 7 Gene3D 1 GeneCards 1 GeneTree 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 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 3 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 2 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 11087757

Title: Multiple isozymes of heparan sulfate/heparin GlcNAc N-deacetylase/GlcN N-sulfotransferase. Structure and activity of the fourth member, NDST4.

PubMed ID: 11087757

DOI: 10.1074/jbc.m009606200

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

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

Sequence Information:

  • Length: 872
  • Mass: 100716
  • Checksum: 9C4E2DD1F98EA859
  • Sequence:
    • MNLIVKLRRS FRTLIVLLAT FCLVSIVISA YFLYSGYKQE MTLIETTAEA ECTDIKILPY 
RSMELKTVKP IDTSKTDPTV LLFVESQYSQ LGQDIIAILE SSRFQYHMVI APGKGDIPPL 
TDNGKGKYTL VIYENILKYV SMDSWNRELL EKYCVEYSVS IIGFHKANEN SLPSTQLKGF 
PLNLFNNLAL KDCFVNPQSP LLHITKAPKV EKGPLPGEDW TIFQYNHSTY QPVLLTELQT 
EKSLSSLSSK TLFATVIQDL GLHDGIQRVL FGNNLNFWLH KLIFIDAISF LSGKRLTLSL 
DRYILVDIDD IFVGKEGTRM NVKDVKALLE TQNLLRTQVA NFTFNLGFSG KFYHTGTEEE 
DEGDDLLLRS VDEFWWFPHM WSHMQPHLFH NESSLVEQMI LNKEFALEHG IPINMGYAVA 
PHHSGVYPVH IQLYAAWKKV WGIQVTSTEE YPHLKPARYR KGFIHNSIMV LPRQTCGLFT 
HTIFYKEYPG GPQELDKSIR GGELFLTILL NPISIFMTHL SNYGNDRLGL YTFVNLVNFV 
QSWTNLKLQT LPPVQLAHQY FELFPEQKDP LWQNPCDDKR HKDIWSREKT CDHLPKFLVI 
GPQKTGTTAL YLFLLMHPSI ISNLPSPKTF EEVQFFNGNN YHKGIDWYMD FFPTPSNTTS 
DFLFEKSANY FHSEEAPRRA ASLVPKAKII TILIDPSDRA YSWYQHQRSH EDPAALRFNF 
YEVISTGHWA PSDLKTLQRR CLVPGWYAVH IERWLTYFAT SQLLIIDGQQ LRSDPATVMD 
EVQKFLGVTP RYNYSEALTF DPQKGFWCQL LEGGKTKCLG KSKGRKYPPM DPESRTFLSN 
YYRDHNVELS KLLHRLGQPL PSWLRQELQK VR

Genular Protein ID: 4209626496

Symbol: A8K0V5_HUMAN

Name: N/A

UniProtKB Accession Codes:

A8K0V5

Database IDs:

ARBA 6 AlphaFoldDB 1 BioGRID-ORCS 1 CTD 1 ChEBI 3 DNASU 1 DisGeNET 1 EMBL 2 GO 5 Gene3D 1 InterPro 4 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PIRSR 3 PeptideAtlas 1 Pfam 4 RefSeq 1 SAM 1 SUPFAM 1 UniPathway 2

Sequence Information:

  • Length: 872
  • Mass: 100689
  • Checksum: 9C4E2DD45D963C74
  • Sequence:
    • MNLIVKLRRS FRTLIVLLAT FCLVSIVISA YFLYSGYKQE MTLIETTAEA ECTDIKILPY 
RSMELKTVKP IDTSKTDPTV LLFVESQYSQ LGQDIIAILE SSRFQYHMVI APGKGDIPPL 
TDNGKGKYTL VIYENILKYV SMDSWNRELL EKYCVEYSVS IIGFHKANEN SLPSTQLKGF 
PLNLFNNLAL KDCFVNPQSP LLHITKAPKV EKGPLPGEDW TIFQYNHSTY QPVLLTELQT 
EKSLSSLSSK TLFATVIQDL GLHDGIQRVL FGNNLNFWLH KLIFIDAISF LSGKRLTLSL 
DRYILVDIDD IFVGKEGTRM NVKDVKALLE TQSLLRTQVA NFTFNLGFSG KFYHTGTEEE 
DEGDDLLLRS VDEFWWFPHM WSHMQPHLFH NESSLVEQMI LNKEFALEHG IPINMGYAVA 
PHHSGVYPVH IQLYAAWKKV WGIQVTSTEE YPHLKPARYR KGFIHNSIMV LPRQTCGLFT 
HTIFYKEYPG GPQELDKSIR GGELFLTILL NPISIFMTHL SNYGNDRLGL YTFVNLVNFV 
QSWTNLKLQT LPPVQLAHQY FELFPEQKDP LWQNPCDDKR HKDIWSREKT CDHLPKFLVI 
GPQKTGTTAL YLFLLMHPSI ISNLPSPKTF EEVQFFNGNN YHKGIDWYMD FFPTPSNTTS 
DFLFEKSANY FHSEEAPRRA ASLVPKAKII TILIDPSDRA YSWYQHQRSH EDPAALRFNF 
YEVISTGHWA PSDLKTLQRR CLVPGWYAVH IERWLTYFAT SQLLIIDGQQ LRSDPATVMD 
EVQKFLGVTP RYNYSEALTF DPQKGFWCQL LEGGKTKCLG KSKGRKYPPM DPESRTFLSN 
YYRDHNVELS KLLHRLGQPL PSWLRQELQK VR