Details for: ART4

Gene ID: 420

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: ART4

Ensembl ID: ENSG00000111339

Description: ADP-ribosyltransferase 4 (inactive) (Dombrock blood group)

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • erythrocyte CL0000232
    CSI 5.23
    rCSI 11.87%
    PRS 79.56
  • midzonal region hepatocyte CL0019028
    CSI 3.76
    rCSI 8.82%
    PRS 79.03
  • hepatic stellate cell CL0000632
    CSI 3.05
    rCSI 11.41%
    PRS 71.1
  • erythroblast CL0000765
    CSI 2.59
    rCSI 6.87%
    PRS 84.79
  • centrilobular region hepatocyte CL0019029
    CSI 2.25
    rCSI 5.87%
    PRS 77.69
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 2.09
    rCSI 6.45%
    PRS 83.16
  • intrahepatic cholangiocyte CL0002538
    CSI 1.97
    rCSI 4.73%
    PRS 83.01
  • periportal region hepatocyte CL0019026
    CSI 1.87
    rCSI 7.29%
    PRS 78.69
  • endocardial cell CL0002350
    CSI 1.87
    rCSI 8.94%
    PRS 75.3
  • hepatocyte CL0000182
    CSI 1.32
    rCSI 2.36%
    PRS 77.91
  • microcirculation associated smooth muscle cell CL0008035
    CSI 0.86
    rCSI 2.5%
    PRS 78.27
  • primitive red blood cell CL0002355
    CSI 0.83
    rCSI 4.49%
    PRS 85.24

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 [ART4](/details-gene/420), or ADP-ribosyltransferase 4, is a protein-coding gene located on chromosome 12 that is best known for encoding the Dombrock blood group antigen ([OMIM: 110600](https://omim.org/entry/110600)). It belongs to a family of enzymes that catalyze the transfer of ADP-ribose to protein substrates, a form of post-translational modification, although its own catalytic activity is debated [Link](https://pubmed.ncbi.nlm.nih.gov/9119374). Functionally, [ART4](/details-gene/420) is a GPI-anchored ecto-enzyme found on the [plasma membrane](/details-ontology/GO:0005886). Expression data reveals its highest significance in [erythrocytes](/details-cell/CL0000232) and their precursors, consistent with its serological role [Link](https://pubmed.ncbi.nlm.nih.gov/11001920). A notable secondary expression signature is observed in various cell types within the liver, suggesting additional, less characterized functions in hepatic biology. ## Cellular Roles and Expression Landscape The expression profile of [ART4](/details-gene/420) strongly defines its primary biological context. **Overall**, the gene exhibits its most significant expression in [erythrocytes](/details-cell/CL0000232) (CSI: 5.23), which aligns with its established identity as the Dombrock blood group glycoprotein. Its high significance is also noted in erythroid precursor cells, including [erythroblasts](/details-cell/CL0000765) and [primitive red blood cells](/details-cell/CL0002355), indicating that its expression is an integral part of erythropoiesis. Beyond the erythroid lineage, [ART4](/details-gene/420) shows a distinct and significant expression pattern within the liver. It is a prominent marker in multiple subpopulations of [hepatocytes](/details-cell/CL0000182), including [midzonal region hepatocytes](/details-cell/CL0019028), [centrilobular region hepatocytes](/details-cell/CL0019029), and [periportal region hepatocytes](/details-cell/CL0019026). Furthermore, its expression is significant in non-parenchymal liver cells such as [hepatic stellate cells](/details-cell/CL0000632) and [endothelial cells of the pericentral hepatic sinusoid](/details-cell/CL0019022). This secondary signature suggests a potential role for [ART4](/details-gene/420) in liver physiology, possibly related to cell-surface protein modification or cell-cell interactions within the hepatic sinusoids. ## Pathways and Molecular Function The functional annotations of [ART4](/details-gene/420) are consistent with its biochemical classification and cellular location. Its molecular function is defined as [NAD+-protein-arginine ADP-ribosyltransferase activity](/details-ontology/GO:0106274), a process involving the covalent attachment of ADP-ribose to arginine residues of target proteins. This activity is a key element of post-translational protein modification, as highlighted by its association with the Reactome pathway [Post-translational protein modification](/details-pathway/R-HSA-597592). As an ecto-enzyme, [ART4](/details-gene/420) is localized to the [extracellular region](/details-ontology/GO:0005576) and tethered to the [plasma membrane](/details-ontology/GO:0005886). This is accomplished via a glycosylphosphatidylinositol (GPI) anchor, a mechanism detailed in the Reactome pathway [Post-translational modification: synthesis of GPI-anchored proteins](/details-pathway/R-HSA-163125). This cell-surface localization allows it to potentially modify other membrane proteins or extracellular substrates, influencing cellular interactions or signaling events in its local environment. ## Research Directions While the role of [ART4](/details-gene/420) as a blood group antigen is well-established, its functional significance, particularly in the liver where it is also highly expressed, remains an open area of investigation. ### Testable Hypotheses 1. The high expression of [ART4](/details-gene/420) across multiple [hepatocyte](/details-cell/CL0000182) populations and sinusoidal cells suggests a functional role in modulating the liver extracellular microenvironment. It may modify cell-surface or secreted proteins, thereby influencing cell-matrix adhesion, growth factor signaling, or lipid metabolism within the liver. 2. On the surface of [erythrocytes](/details-cell/CL0000232), [ART4](/details-gene/420) may possess context-dependent enzymatic activity that targets specific membrane proteins, potentially modulating erythrocyte membrane integrity, flexibility, or interactions with endothelial cells, thereby contributing to vascular homeostasis or pathology. ### Key Experiments To test the hypothesis regarding the function of [ART4](/details-gene/420) in the liver, a multi-pronged approach could be employed. First, CRISPR-Cas9-mediated knockout of [ART4](/details-gene/420) in a human hepatocyte cell line (e.g., HepG2) or in primary human hepatocytes would be a critical first step. The surface proteome of these knockout cells could then be compared to wild-type cells using mass spectrometry to identify potential protein substrates that exhibit altered ADP-ribosylation patterns. Functional consequences could be assessed via cell adhesion assays, analysis of secreted protein profiles (secretomics), and measurement of key metabolic functions such as albumin secretion and cytochrome P450 activity. ### Therapeutic Potential The primary clinical relevance of [ART4](/details-gene/420) is in transfusion medicine, where polymorphisms define the Dombrock blood group system and can be associated with transfusion reactions [Link](https://doi.org/10.1046/j.1537-2995.2002.00004.x). As a therapeutic target, its high and relatively specific expression on [erythrocytes](/details-cell/CL0000232) makes it an attractive candidate for antibody-based therapies. For diseases involving red blood cells, such as certain parasitic infections (e.g., malaria) or autoimmune hemolytic anemias, [ART4](/details-gene/420) could serve as a target for cell-specific drug delivery or for therapeutic antibodies designed to induce targeted cell clearance. However, its significant expression in the liver presents a potential for off-target effects that would need to be carefully evaluated for any systemic therapeutic strategy. The therapeutic approach would likely involve inhibition or targeted depletion rather than activation.

Genular Protein ID: 716767119

Symbol: NAR4_HUMAN

Name: Ecto-ADP-ribosyltransferase 4

UniProtKB Accession Codes:

Q93070 Q9BZ50 Q9BZ51 Q9HB06

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 8 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 2 EMBL 22 Ensembl 1 ExpressionAtlas 1 GO 7 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 2 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 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 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 11001920

Title: Identification of the Dombrock blood group glycoprotein as a polymorphic member of the ADP-ribosyltransferase gene family.

PubMed ID: 11001920

PubMed ID: 11896313

Title: Insights into the Holley- and Joseph- phenotypes.

PubMed ID: 11896313

DOI: 10.1046/j.1537-2995.2002.00004.x

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

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: 9119374

Title: Two novel human members of an emerging mammalian gene family related to mono-ADP-ribosylating bacterial toxins.

PubMed ID: 9119374

DOI: 10.1006/geno.1996.4520

PubMed ID: 11520417

Title: Polymerase chain reaction with sequence-specific primers-based genotyping of the human Dombrock blood group DO1 and DO2 alleles and the DO gene frequencies in Chinese blood donors.

PubMed ID: 11520417

DOI: 10.1046/j.1423-0410.2001.00052.x

PubMed ID: 20106667

Title: Toward a unified nomenclature for mammalian ADP-ribosyltransferases.

PubMed ID: 20106667

DOI: 10.1016/j.tibs.2009.12.003

Sequence Information:

  • Length: 314
  • Mass: 35879
  • Checksum: 1744A8E4B7FD158F
  • Sequence:
    • MGPLINRCKK ILLPTTVPPA TMRIWLLGGL LPFLLLLSGL QRPTEGSEVA IKIDFDFAPG 
SFDDQYQGCS KQVMEKLTQG DYFTKDIEAQ KNYFRMWQKA HLAWLNQGKV LPQNMTTTHA 
VAILFYTLNS NVHSDFTRAM ASVARTPQQY ERSFHFKYLH YYLTSAIQLL RKDSIMENGT 
LCYEVHYRTK DVHFNAYTGA TIRFGQFLST SLLKEEAQEF GNQTLFTIFT CLGAPVQYFS 
LKKEVLIPPY ELFKVINMSY HPRGDWLQLR STGNLSTYNC QLLKASSKKC IPDPIAIASL 
SFLTSVIIFS KSRV