Details for: PCDHGC4

Gene ID: 56098

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: PCDHGC4

Ensembl ID: ENSG00000242419

Description: protocadherin gamma subfamily C, 4

Cell Significance Landscape

Associated with

Significant Cells

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

  • neural progenitor cell CL0011020
    CSI 4.84
    rCSI 21.29%
    PRS 99.75

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

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  • Node Color (Target Cell CSI, relative to current network):
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  • 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 Analyzed for its expression specificity (CSI Z-Score), [PCDHGC4](/details-gene/56098) is a member of the protocadherin gamma gene cluster, a family of calcium-dependent cell-adhesion proteins. Its function is primarily associated with nervous system development, specifically in mediating homophilic cell-cell interactions. While data suggests a highly restricted expression pattern in specific neural lineages, its statistical significance as a marker in a broad context requires further investigation. Pathogenic variants in [PCDHGC4](/details-gene/56098) are linked to a severe neurodevelopmental syndrome, highlighting its critical role in human brain development. ## Cellular Roles and Expression Landscape The expression profile of [PCDHGC4](/details-gene/56098), when evaluated for specificity, points towards a highly specialized role. In the **Overall** context, its expression appears most distinct in [neural progenitor cells](/details-cell/CL0011020). This is supported by a maximal Effect Size (1.00), which indicates that its expression is highly confined to this cell type relative to others in the dataset. However, this observation is accompanied by a non-significant p-value (0.439) and a CSI (Z-SCORE) of 0.00, suggesting that while its expression is restricted, it does not achieve statistical power as a top-tier specificity marker in this broad analysis. The high Percentile Rank Score (PRS: 99.75%) suggests it still ranks among the most specific genes, but the lack of statistical significance may be due to factors such as low overall expression levels or high variance. This pattern is consistent with its known function as a protocadherin, a class of molecules crucial for establishing specific neuronal connections during development, a process that would require precise expression in progenitor and developing neuronal populations. ## Pathways and Molecular Function The functional annotations for [PCDHGC4](/details-gene/56098) align perfectly with its role as a cell adhesion molecule in the nervous system. It is a key participant in [homophilic cell adhesion via plasma membrane adhesion molecules](/details-cell/GO:0007156) and the broader process of [cell adhesion](/details-cell/GO:0007155). This function is critical for processes like [nervous system development](/details-cell/GO:0007399) and [synapse organization](/details-cell/GO:0050808), as described in foundational work on the protocadherin family ([PubMed: 10380929](https://pubmed.ncbi.nlm.nih.gov/10380929/)). As a member of the cadherin superfamily, its function is dependent on [calcium ion binding](/details-cell/GO:0005509), which mediates the conformational changes required for cell-cell binding. Its localization to the [plasma membrane](/details-cell/GO:0005886) is essential for this role. Clinically, the importance of these functions is underscored by the finding that biallelic variants in [PCDHGC4](/details-gene/56098) cause a neurodevelopmental syndrome characterized by microcephaly and seizures, strongly suggesting that its adhesive function is non-redundant and essential for proper brain formation ([PubMed: 34244665](https://doi.org/10.1038/s41436-021-01260-4)). ## Research Directions The specific expression pattern of [PCDHGC4](/details-gene/56098) in [neural progenitor cells](/details-cell/CL0011020), combined with its established link to a severe neurodevelopmental disorder, opens several avenues for future research. ### Proposed Testable Hypotheses 1. **Hypothesis:** [PCDHGC4](/details-gene/56098) is essential for maintaining the structural integrity and signaling environment of the neural progenitor cell niche. Its homophilic binding may prevent premature delamination and differentiation of progenitors during corticogenesis. * **Experimental Approach:** Utilize CRISPR/Cas9 to knock out [PCDHGC4](/details-gene/56098) in human iPSC-derived cortical organoids. Analyze the cytoarchitecture of the ventricular zone, progenitor cell proliferation rates (e.g., Ki67 staining), and the onset of neuronal differentiation (e.g., DCX, Tuj1 staining) using advanced microscopy and single-cell RNA sequencing. 2. **Hypothesis:** The lack of a strong statistical signature (CSI Z-Score) in the **Overall** context, despite high specificity (Effect Size), suggests functional compensation by other co-expressed gamma-protocadherins. The loss of [PCDHGC4](/details-gene/56098) alone may be partially buffered by other family members like `PCDHGC3` or `PCDHGC5`. * **Experimental Approach:** Perform combinatorial siRNA or CRISPRi-mediated knockdown of [PCDHGC4](/details-gene/56098) along with other gamma-protocadherins in primary neural progenitor cultures. Assess cell aggregation, survival, and neurite outgrowth upon differentiation, comparing single vs. combinatorial knockdowns to reveal synergistic functional deficits. 3. **Hypothesis:** Pathogenic mutations identified in patients ([PubMed: 34244665](https://doi.org/10.1038/s41436-021-01260-4)) disrupt the extracellular cadherin (EC) domains, specifically impairing calcium-dependent homophilic adhesion and leading to failed cell sorting and neuronal migration defects. * **Experimental Approach:** Engineer cell lines (e.g., K562 cells, which lack endogenous cadherins) to express wild-type or patient-specific mutant forms of [PCDHGC4](/details-gene/56098). Perform quantitative cell aggregation assays in the presence and absence of calcium to directly measure the impact of these mutations on adhesion strength. ### Therapeutic Potential Given its monogenic link to a severe neurodevelopmental syndrome, [PCDHGC4](/details-gene/56098) represents a potential target for gene replacement therapy. Restoring functional [PCDHGC4](/details-gene/56098) expression in neural progenitors during early development could theoretically mitigate the severe outcomes of the disease. Furthermore, a deeper understanding of its cell-adhesive role could inform strategies for improving the integration of transplanted neural stem cells in regenerative medicine applications.

Genular Protein ID: 3756919928

Symbol: PCDGL_HUMAN

Name: Protocadherin gamma-C4

UniProtKB Accession Codes:

Q9Y5F7 Q495T2 Q9Y5C3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 5 Ensembl 2 ExpressionAtlas 1 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 6 KEGG 1 MANE-Select 1 MIM 4 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 RefSeq 2 SIGNOR 1 SMART 1 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: 10380929

Title: A striking organization of a large family of human neural cadherin-like cell adhesion genes.

PubMed ID: 10380929

DOI: 10.1016/s0092-8674(00)80789-8

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: 34244665

Title: Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies.

PubMed ID: 34244665

DOI: 10.1038/s41436-021-01260-4

Sequence Information:

  • Length: 938
  • Mass: 101214
  • Checksum: 99820B82A2F18ECC
  • Sequence:
    • MLRKVRSWTE IWRWATLLFL FYHLGYVCGQ IRYPVPEESQ EGTFVGNVAQ DFLLDTDSLS 
ARRLQVAGEV NQRHFRVDLD SGALLIKNPI DREALCGLSA SCIVPLEFVT EGPLEMYRAE 
VEIVDVNDHA PRFPRQQLDL EIGEAAPPGQ RFPLEKAQDA DVGSNSISSY RLSSNEHFAL 
DVKKRSDGSL VPELLLEKPL DREKQSDYRL VLTAVDGGNP PRSGTAELRV SVLDVNDNAP 
AFQQSSYRIS VLESAPAGMV LIQLNASDPD LGPSGNVTFY FSGHTPDRVR NLFSLHPTTG 
KLTLLGPLDF ESENYYEFDV RARDGGSPAM EQHCSLRVDL LDVNDNAPYI TVTSELGTLP 
ESAEPGTVVA LISVQDPDSG SNGDVSLRIP DHLPFALKSA FRNQFSLVTA GPLDREAKSS 
YDIMVTASDA GNPPLSTHRT IFLNISDVND NPPSFFQRSH EVFVPENNRP GDLLCSLAAS 
DPDSGLNALI SYSLLEPRNR DVSASSFISL NPQTGAVHAT RSFDYEQTQT LQFEVQARDR 
GNPPLSSTVT VRLFVLDLND NAPAVLRPRA RPGSLCPQAL PPSVGAGHLI TKVTAVDLDS 
GYNAWVSYQL LEAPDPSLFA VSRYAGEVRT AVPIPADLPP QKLVIVVKDS GSPPLSTSVT 
LLVSLEEDTH PVVPDLRESS APREGESRLT LYLAVSLVAI CFVSFGSFVA LLSKCLRGAA 
CGVTCFPAGT CACLTRSRRR EGLPPSNGIL RIQLGSDDPI KFVDVGGHSH GCTPLASAPT 
RSDSFMMVKS PSAPMAGEPV RPSCPPSDLL YGLEQAPPNT DWRFSQAQRP GTSGSQNGDD 
TGTWPNNQFD TEMLQAMILA SASEAADGSS TLGGGAGTMG LSARYGPQFT LQHVPDYRQN 
VYIPGSNATL TNAAGKRDGK APAGGNGNKK KSGKKEKK