Details for: GPC4

Gene ID: 2239

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: GPC4

Ensembl ID: ENSG00000076716

Description: glypican 4

Cell Significance Landscape

Associated with

Significant Cells

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

  • parietal epithelial cell CL1000452
    CSI 12.06
    rCSI 32.22%
    PRS 87.2
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 11.47
    rCSI 16.26%
    PRS 90.01
  • epithelial cell of lung CL0000082
    CSI 6.88
    rCSI 5.7%
    PRS 92.72
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 6.2
    rCSI 7.95%
    PRS 88.36
  • stromal cell CL0000499
    CSI 5.16
    rCSI 14.51%
    PRS 88.36
  • glioblast CL0000030
    CSI 3.87
    rCSI 6.18%
    PRS 84.96
  • neural crest cell CL0011012
    CSI 3.85
    rCSI 3.04%
    PRS 85.6
  • interstitial cell of Cajal CL0002088
    CSI 3.52
    rCSI 4.48%
    PRS 94.8
  • Bergmann glial cell CL0000644
    CSI 3.48
    rCSI 4.76%
    PRS 85.06
  • epithelial cell of lower respiratory tract CL0002632
    CSI 3.47
    rCSI 2.69%
    PRS 93.83
  • fibroblast of lung CL0002553
    CSI 3.25
    rCSI 3.02%
    PRS 93.08
  • hepatic stellate cell CL0000632
    CSI 3.04
    rCSI 11.39%
    PRS 88.01
  • extravillous trophoblast CL0008036
    CSI 2.83
    rCSI 3.5%
    PRS 90.38
  • mesodermal cell CL0000222
    CSI 2.68
    rCSI 3.22%
    PRS 90.79
  • lung ciliated cell CL1000271
    CSI 2.59
    rCSI 3%
    PRS 86.83
  • cerebral cortex endothelial cell CL1001602
    CSI 2.57
    rCSI 4.45%
    PRS 86.97
  • ependymal cell CL0000065
    CSI 2.46
    rCSI 4.99%
    PRS 75.46
  • respiratory suprabasal cell CL4033048
    CSI 2.37
    rCSI 3.04%
    PRS 93.2
  • epithelial cell of proximal tubule CL0002306
    CSI 2.36
    rCSI 5.76%
    PRS 86
  • radial glial cell CL0000681
    CSI 2.35
    rCSI 3.27%
    PRS 90.38
  • elicited macrophage CL0000861
    CSI 2.3
    rCSI 2.12%
    PRS 95.45
  • vascular leptomeningeal cell CL4023051
    CSI 2.17
    rCSI 3.8%
    PRS 88.73
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 2.15
    rCSI 2.49%
    PRS 84.87
  • pulmonary alveolar type 2 cell CL0002063
    CSI 2
    rCSI 3.1%
    PRS 92.44
  • enteric smooth muscle cell CL0002504
    CSI 1.98
    rCSI 2.83%
    PRS 91.78
  • lung secretory cell CL1000272
    CSI 1.91
    rCSI 4.74%
    PRS 92.51
  • vascular associated smooth muscle cell CL0000359
    CSI 1.9
    rCSI 6.17%
    PRS 90.13
  • fallopian tube secretory epithelial cell CL4030006
    CSI 1.84
    rCSI 1.77%
    PRS 90.4
  • Schwann cell CL0002573
    CSI 1.82
    rCSI 5.18%
    PRS 88.52
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.7
    rCSI 4.32%
    PRS 86.45
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.68
    rCSI 3.76%
    PRS 80.43
  • lung pericyte CL0009089
    CSI 1.65
    rCSI 4.36%
    PRS 95.09
  • renal interstitial pericyte CL1001318
    CSI 1.57
    rCSI 4.33%
    PRS 89.52
  • tracheobronchial smooth muscle cell CL0019019
    CSI 1.55
    rCSI 2.73%
    PRS 94.24
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.53
    rCSI 3.95%
    PRS 89.6
  • forebrain radial glial cell CL0013000
    CSI 1.51
    rCSI 4.86%
    PRS 91.53
  • mesenchymal cell CL0008019
    CSI 1.39
    rCSI 3.53%
    PRS 87.28
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.39
    rCSI 2.45%
    PRS 79.53
  • cardiac neuron CL0010022
    CSI 1.17
    rCSI 3.75%
    PRS 90.68
  • neural progenitor cell CL0011020
    CSI 1.16
    rCSI 5.12%
    PRS 81.98
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.63
    rCSI 2.25%
    PRS 78.17
  • kidney loop of Henle thick ascending limb epithelial cell CL1001106
    CSI 0.55
    rCSI 4.76%
    PRS 86.76
  • bronchiolar smooth muscle cell CL4033017
    CSI 0.5
    rCSI 7.52%
    PRS 95.08

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.

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 [GPC4](/details-gene/2239) (glypican 4) is a protein-coding gene located on the X chromosome that encodes a member of the glypican family of heparan sulfate proteoglycans. These proteins are anchored to the external surface of the plasma membrane and function as coreceptors for a variety of signaling molecules, most notably in the [Wnt signaling pathway](/details-cell/GO:0016055). Expression data indicates that **`Overall`**, [GPC4](/details-gene/2239) is a significant marker for specialized epithelial cells, particularly [parietal epithelial cell](/details-cell/CL1000452) in the kidney and [epithelial cell of lung](/details-cell/CL0000082), as well as for certain neural progenitor cells like [neuroblast (sensu Vertebrata)](/details-cell/CL0000031). Clinically, pathogenic variants in [GPC4](/details-gene/2239) are associated with several developmental disorders, including Keipert Syndrome ([301026](https://omim.org/entry/301026)) [Link](https://doi.org/10.1016/j.ajhg.2019.02.026), and deletions of the GPC3-GPC4 gene cluster are linked to Simpson-Golabi-Behmel syndrome ([312870](https://omim.org/entry/312870)) [Link](https://doi.org/10.1006/geno.1998.5465). ## Cellular Roles and Expression Landscape The expression profile of [GPC4](/details-gene/2239) highlights its significant role in specific cellular contexts, primarily within epithelial and neural lineages. **`Overall`**, the gene shows the highest significance in renal epithelial cells, including [parietal epithelial cell](/details-cell/CL1000452) (CSI: 12.06) and [kidney loop of Henle thin descending limb epithelial cell](/details-cell/CL1001111) (CSI: 11.47), suggesting a crucial function in kidney development or physiology. A second major functional niche appears to be in the respiratory system, with high significance in [epithelial cell of lung](/details-cell/CL0000082) (CSI: 6.88) and [epithelial cell of lower respiratory tract](/details-cell/CL0002632) (CSI: 3.47). This is complemented by its expression in associated structural cells like [fibroblast of lung](/details-cell/CL0002553) (CSI: 3.25). Furthermore, [GPC4](/details-gene/2239) is prominently expressed in the developing nervous system. Its high significance in [neuroblast (sensu Vertebrata)](/details-cell/CL0000031) (CSI: 6.20), [glioblast](/details-cell/CL0000030) (CSI: 3.87), [neural crest cell](/details-cell/CL0011012) (CSI: 3.85), and [Bergmann glial cell](/details-cell/CL0000644) (CSI: 3.48) points toward a role in neurogenesis, cell migration, and glial function. The expression in diverse cell types such as [stromal cell](/details-cell/CL0000499) and [hepatic stellate cell](/details-cell/CL0000632) suggests broader roles in tissue architecture and signaling across multiple organ systems. ## Pathways and Molecular Function Functionally, [GPC4](/details-gene/2239) acts as a [coreceptor](/details-cell/GO:0015026) on the [cell surface](/details-cell/GO:0009986), consistent with its localization to the [external side of plasma membrane](/details-cell/GO:0009897). Its primary role involves modulating signal transduction pathways, particularly the [Wnt signaling pathway](/details-cell/GO:0016055), which is critical for embryonic development and tissue homeostasis. This is consistent with its association with developmental disorders like Robinow syndrome and Keipert Syndrome [Link](https://doi.org/10.1016/j.ajhg.2019.02.026), [Link](https://doi.org/10.1016/j.ajhg.2017.10.002). The gene is deeply involved in [heparan sulfate/heparin (hs-gag) metabolism](/details-cell/R-HSA-1638091), a process fundamental to its structure and function as a proteoglycan. This metabolic role is highlighted by numerous associated Reactome pathways, including [Hs-gag biosynthesis](/details-cell/R-HSA-2022928) and its link to diseases of glycosylation. Interestingly, functional annotations also strongly implicate [GPC4](/details-gene/2239) in host-pathogen interactions. Reactome pathways for [Sars-cov-2 infection](/details-cell/R-HSA-9694516) and [Respiratory syncytial virus (rsv) infection pathway](/details-cell/R-HSA-9820952) suggest that the GPC4 protein may serve as an attachment factor or coreceptor that facilitates viral entry into host cells. This aligns with its high expression in lung epithelial cells, the primary target for these viruses. Its role in [cell migration](/details-cell/GO:0016477) and [synaptic membrane adhesion](/details-cell/GO:0099560) further supports its function in tissue development and neural connectivity. ## Research Directions The diverse expression pattern and functional annotations of [GPC4](/details-gene/2239) suggest several avenues for future research. Its prominent role in both developmental signaling and host-pathogen interactions makes it a gene of significant interest. ### Proposed Hypotheses: 1. **Role in Renal Homeostasis:** Given its exceptionally high expression in specific kidney epithelial cells, [GPC4](/details-gene/2239) may be essential for maintaining the structural integrity and function of the renal tubules. Its dysregulation via Wnt signaling modulation could be a contributing factor to the progression of chronic kidney disease or fibrosis following injury. 2. **Facilitator of Viral Entry:** The convergence of high expression in [epithelial cell of lung](/details-cell/CL0000082) and its annotated role in [Sars-cov-2 infection](/details-cell/R-HSA-9694516) pathways suggests that [GPC4](/details-gene/2239) functions as a host coreceptor for respiratory viruses. Variation in [GPC4](/details-gene/2239) expression levels in the lung epithelium may correlate with an individual's susceptibility to or severity of viral infections like COVID-19. 3. **Regulator of Synaptogenesis:** Based on its expression in neural progenitors and its involvement in synaptic adhesion ([GO:0099560](https://www.ebi.ac.uk/QuickGO/term/GO:0099560)), [GPC4](/details-gene/2239) likely plays a critical role in synapse formation and stabilization during neural development. The neurological features of GPC4-related syndromes could stem from defects in this process. ### Key Experimental Approach: To test the hypothesis that [GPC4](/details-gene/2239) acts as a coreceptor for respiratory viruses, an *in vitro* infection model could be employed. Specifically, CRISPR-Cas9 could be used to generate a [GPC4](/details-gene/2239) knockout in a human lung epithelial cell line (e.g., Calu-3). Wild-type and knockout cells would then be infected with pseudotyped viral particles expressing the SARS-CoV-2 Spike protein and a reporter gene (e.g., luciferase). A significant reduction in reporter gene activity in the knockout cells compared to the wild-type control would provide strong evidence for the role of [GPC4](/details-gene/2239) in viral entry. ### Therapeutic Potential: As a cell-surface protein, [GPC4](/details-gene/2239) is a highly accessible therapeutic target. In the context of viral infections, it represents a promising target for **inhibition**. Strategies could include the development of monoclonal antibodies that block the viral binding site on [GPC4](/details-gene/2239) or the use of soluble recombinant [GPC4](/details-gene/2239) as a decoy to neutralize virions before they reach host cells. However, given its important roles in development and tissue maintenance, particularly in the kidney, any systemic inhibitory therapy would require careful evaluation for potential adverse effects.

Genular Protein ID: 2196732389

Symbol: GPC4_HUMAN

Name: Glypican-4

UniProtKB Accession Codes:

O75487 B2R6J7 B4E2C0 Q6ZMA6 Q96L43 Q9NU08 Q9UJN1 Q9UPD9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 10 Ensembl 1 GO 17 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 12 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9787072

Title: GPC4, the gene for human K-glypican, flanks GPC3 on Xq26: deletion of the GPC3-GPC4 gene cluster in one family with Simpson-Golabi-Behmel syndrome.

PubMed ID: 9787072

DOI: 10.1006/geno.1998.5465

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15772651

Title: The DNA sequence of the human X chromosome.

PubMed ID: 15772651

DOI: 10.1038/nature03440

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: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 10814714

Title: Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene.

PubMed ID: 10814714

DOI: 10.1093/hmg/9.9.1321

PubMed ID: 29276006

Title: WNT signaling perturbations underlie the genetic heterogeneity of Robinow syndrome.

PubMed ID: 29276006

DOI: 10.1016/j.ajhg.2017.10.002

PubMed ID: 30982611

Title: Pathogenic variants in GPC4 cause Keipert Syndrome.

PubMed ID: 30982611

DOI: 10.1016/j.ajhg.2019.02.026

Sequence Information:

  • Length: 556
  • Mass: 62412
  • Checksum: 827E07FAA0BD8188
  • Sequence:
    • MARFGLPALL CTLAVLSAAL LAAELKSKSC SEVRRLYVSK GFNKNDAPLH EINGDHLKIC 
PQGSTCCSQE MEEKYSLQSK DDFKSVVSEQ CNHLQAVFAS RYKKFDEFFK ELLENAEKSL 
NDMFVKTYGH LYMQNSELFK DLFVELKRYY VVGNVNLEEM LNDFWARLLE RMFRLVNSQY 
HFTDEYLECV SKYTEQLKPF GDVPRKLKLQ VTRAFVAART FAQGLAVAGD VVSKVSVVNP 
TAQCTHALLK MIYCSHCRGL VTVKPCYNYC SNIMRGCLAN QGDLDFEWNN FIDAMLMVAE 
RLEGPFNIES VMDPIDVKIS DAIMNMQDNS VQVSQKVFQG CGPPKPLPAG RISRSISESA 
FSARFRPHHP EERPTTAAGT SLDRLVTDVK EKLKQAKKFW SSLPSNVCND ERMAAGNGNE 
DDCWNGKGKS RYLFAVTGNG LANQGNNPEV QVDTSKPDIL ILRQIMALRV MTSKMKNAYN 
GNDVDFFDIS DESSGEGSGS GCEYQQCPSE FDYNATDHAG KSANEKADSA GVRPGAQAYL 
LTVFCILFLV MQREWR