Details for: EPB42

Gene ID: 2038

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: EPB42

Ensembl ID: ENSG00000166947

Description: erythrocyte membrane protein band 4.2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • subcutaneous adipocyte CL0002521
    CSI 5.47
    rCSI 28.02%
    PRS 96.31
  • erythrocyte CL0000232
    CSI 4.72
    rCSI 10.71%
    PRS 93.55
  • primitive red blood cell CL0002355
    CSI 4.28
    rCSI 23.09%
    PRS 95.7
  • adipocyte CL0000136
    CSI 2.92
    rCSI 3.74%
    PRS 89.7
  • elicited macrophage CL0000861
    CSI 2.72
    rCSI 2.49%
    PRS 97.92
  • contractile cell CL0000183
    CSI 2.64
    rCSI 7.78%
    PRS 95.44
  • cerebellar granule cell CL0001031
    CSI 2.61
    rCSI 3.84%
    PRS 92.01
  • monocyte CL0000576
    CSI 2.53
    rCSI 4.58%
    PRS 96.1
  • Bergmann glial cell CL0000644
    CSI 2.52
    rCSI 3.45%
    PRS 90.26
  • erythroid lineage cell CL0000764
    CSI 2.27
    rCSI 14.62%
    PRS 95.89
  • neural cell CL0002319
    CSI 2.09
    rCSI 7.9%
    PRS 85.47
  • alveolar macrophage CL0000583
    CSI 1.95
    rCSI 3.21%
    PRS 96.25
  • retinal ganglion cell CL0000740
    CSI 1.48
    rCSI 3.26%
    PRS 88.35
  • erythroblast CL0000765
    CSI 1.43
    rCSI 3.79%
    PRS 95.18
  • GABAergic neuron CL0000617
    CSI 1.37
    rCSI 4.6%
    PRS 85.59
  • erythroid progenitor cell CL0000038
    CSI 0.42
    rCSI 2.39%
    PRS 96.29

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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  • 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 [EPB42](/details-gene/2038), or erythrocyte membrane protein band 4.2, is a protein-coding gene located on chromosome 15q15.2. It encodes a major component of the [erythrocyte](/details-cell/CL0000232) plasma membrane cytoskeleton, playing a crucial role in maintaining cell shape and mechanical stability. Functionally, it is involved in [cytoskeleton organization](/details-go/GO:0007010) and exhibits [protein-glutamine gamma-glutamyltransferase activity](/details-go/GO:0003810). Expression data reveals its highest significance in erythroid lineage cells, including [erythrocyte](/details-cell/CL0000232)s and [primitive red blood cell](/details-cell/CL0002355)s, consistent with its canonical function. However, its significant expression in [subcutaneous adipocyte](/details-cell/CL0002521)s suggests a less-characterized role in other tissues. Clinically, mutations in [EPB42](/details-gene/2038) are associated with hereditary hemolytic anemia ([177070](https://omim.org/entry/177070)), a condition characterized by abnormally shaped red blood cells. ## Cellular Roles and Expression Landscape The expression profile of [EPB42](/details-gene/2038) strongly underscores its primary function in erythropoiesis and red blood cell biology. **Overall**, the gene shows its highest significance in cells of the erythroid lineage, including [erythrocyte](/details-cell/CL0000232) (CSI: 4.72), [primitive red blood cell](/details-cell/CL0002355) (CSI: 4.28), [erythroid lineage cell](/details-cell/CL0000764) (CSI: 2.27), and [erythroblast](/details-cell/CL0000765) (CSI: 1.43). This expression pattern is consistent with its established role in [erythrocyte maturation](/details-go/GO:0043249) and maintaining the structural integrity of the red blood cell membrane. Intriguingly, the highest significance index for [EPB42](/details-gene/2038) is observed in [subcutaneous adipocyte](/details-cell/CL0002521) (CSI: 5.47), with high scores also seen in general [adipocyte](/details-cell/CL0000136)s (CSI: 2.92). This suggests a potential, yet poorly defined, function in adipocyte biology, possibly related to cytoskeletal architecture or membrane stability in these lipid-storage cells. Furthermore, [EPB42](/details-gene/2038) shows notable significance in several myeloid and neural cell types. Its expression in [elicited macrophage](/details-cell/CL0000861) (CSI: 2.72), [monocyte](/details-cell/CL0000576) (CSI: 2.53), and [alveolar macrophage](/details-cell/CL0000583) (CSI: 1.95) may suggest a role related to erythrophagocytosis or other immune functions. Expression is also detected in diverse neural cells such as [cerebellar granule cell](/details-cell/CL0001031) (CSI: 2.61) and [Bergmann glial cell](/details-cell/CL0000644) (CSI: 2.52), indicating that its function may extend beyond the hematopoietic system. ## Pathways and Molecular Function [EPB42](/details-gene/2038) is fundamentally a structural protein that contributes to the stability of the cell membrane. According to Gene Ontology annotations, it is a [structural constituent of cytoskeleton](/details-go/GO:0005200) located at the [plasma membrane](/details-go/GO:0005886), specifically within the [cortical cytoskeleton](/details-go/GO:0030863). Recent research has confirmed its role as a key component of the [Ankyrin-1 complex](/details-go/GO:0170014), which anchors the spectrin-based cytoskeleton to the erythrocyte membrane ([Link](https://doi.org/10.1038/s41594-022-00792-w)). The molecular functions of the [EPB42](/details-gene/2038) protein include [protein binding](/details-go/GO:0005515) and [protein-glutamine gamma-glutamyltransferase activity](/details-go/GO:0003810). This enzymatic activity facilitates [peptide cross-linking](/details-go/GO:0018149), which likely contributes to the stabilization of cytoskeletal protein networks. These molecular activities are integral to biological processes such as [regulation of cell shape](/details-go/GO:0008360) and [cell morphogenesis](/details-go/GO:0000902), which are critical for the function of deformable cells like erythrocytes. Its importance in systemic physiology is also highlighted by its involvement in [multicellular organismal-level iron ion homeostasis](/details-go/GO:0060586) and [spleen development](/details-go/GO:0048536), processes closely tied to red blood cell turnover. ## Research Directions The well-defined role of [EPB42](/details-gene/2038) in hereditary hemolytic anemias provides a solid foundation for research, but its expression in non-erythroid cells opens new avenues of investigation. Numerous studies have linked specific point mutations to disease, such as the alanine-to-threonine substitution in protein 4.2 Nippon ([Link](https://pubmed.ncbi.nlm.nih.gov/1558976/)) and other mutations causing protein deficiency and microspherocytosis ([Link](https://doi.org/10.1111/j.1365-2141.1995.tb05299.x)). Understanding the molecular consequences of these mutations remains a key research area. Based on the available data, several testable hypotheses can be proposed: 1. The high significance of [EPB42](/details-gene/2038) in [subcutaneous adipocyte](/details-cell/CL0002521)s suggests it performs a structural role analogous to its function in erythrocytes. We hypothesize that [EPB42](/details-gene/2038) is critical for maintaining the mechanical integrity and cytoskeletal organization of adipocytes, particularly under conditions of lipid loading and unloading. 2. The expression of [EPB42](/details-gene/2038) in [monocyte](/details-cell/CL0000576)s and [macrophage](/details-cell/CL0000861)s may be linked to their function in clearing senescent erythrocytes. It is hypothesized that [EPB42](/details-gene/2038) on the macrophage surface could act as a receptor or co-receptor that recognizes and binds to ligands on aged red blood cells, thereby facilitating erythrophagocytosis. To test the first hypothesis regarding the role of [EPB42](/details-gene/2038) in adipocytes, a key experiment would be to use CRISPR-Cas9 to knock out the gene in a human pre-adipocyte cell line. After inducing differentiation into mature adipocytes, the impact on cellular function could be assessed. Assays would include high-resolution imaging to evaluate cell morphology and lipid droplet size, atomic force microscopy to measure cell membrane stiffness, and functional assays to quantify lipolysis rates in response to hormonal stimulation. Given that hereditary hemolytic anemia associated with [EPB42](/details-gene/2038) is a monogenic, loss-of-function disorder, the gene represents a potential target for gene therapy. A therapeutic strategy would aim at restoring functional protein expression in hematopoietic stem cells, rather than inhibiting a protein's activity. The primary challenge would be developing safe and efficient delivery systems for corrective gene constructs to the relevant cell populations. Its widespread, albeit lower-level, expression in other tissues like adipose and neural cells would require careful consideration to avoid off-target effects.

Genular Protein ID: 3463095345

Symbol: EPB42_HUMAN

Name: N/A

UniProtKB Accession Codes:

P16452 Q4KKX0 Q4VB97

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 21 EMDB 13 Ensembl 2 ExpressionAtlas 1 GO 13 Gene3D 2 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 11 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 13 PDBsum 13 PIR 1 PIRSF 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 RefSeq 5 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2052563

Title: Organization of the gene for human erythrocyte membrane protein 4.2: structural similarities with the gene for the a subunit of factor XIII.

PubMed ID: 2052563

DOI: 10.1073/pnas.88.11.4840

PubMed ID: 2300550

Title: Complete amino acid sequence and homologies of human erythrocyte membrane protein band 4.2.

PubMed ID: 2300550

DOI: 10.1073/pnas.87.2.613

PubMed ID: 1689063

Title: Molecular cloning of human protein 4.2: a major component of the erythrocyte membrane.

PubMed ID: 1689063

DOI: 10.1073/pnas.87.3.955

PubMed ID: 16572171

Title: Analysis of the DNA sequence and duplication history of human chromosome 15.

PubMed ID: 16572171

DOI: 10.1038/nature04601

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: 1544941

Title: Human erythrocyte protein 4.2, a high copy number membrane protein, is N-myristylated.

PubMed ID: 1544941

DOI: 10.1016/s0021-9258(18)42820-7

PubMed ID: 8499466

Title: Structural domain mapping and phosphorylation of human erythrocyte pallidin (band 4.2).

PubMed ID: 8499466

DOI: 10.1016/0005-2736(93)90156-t

PubMed ID: 35835865

Title: Architecture of the human erythrocyte ankyrin-1 complex.

PubMed ID: 35835865

DOI: 10.1038/s41594-022-00792-w

PubMed ID: 1558976

Title: An alanine-to-threonine substitution in protein 4.2 cDNA is associated with a Japanese form of hereditary hemolytic anemia (protein 4.2 Nippon).

PubMed ID: 1558976

PubMed ID: 7819064

Title: A novel mutation in the erythrocyte protein 4.2 gene of Japanese patients with hereditary spherocytosis (protein 4.2 Fukuoka).

PubMed ID: 7819064

DOI: 10.1111/j.1365-2141.1994.tb05069.x

PubMed ID: 7772513

Title: A point mutation in the protein 4.2 gene (allele 4.2 Tozeur) associated with hereditary haemolytic anaemia.

PubMed ID: 7772513

DOI: 10.1111/j.1365-2141.1995.tb08413.x

PubMed ID: 8547071

Title: Band 4.2 Shiga: 317 CGC-->TGC in compound heterozygotes with 142 GCT-->ACT results in band 4.2 deficiency and microspherocytosis.

PubMed ID: 8547071

DOI: 10.1111/j.1365-2141.1995.tb05299.x

PubMed ID: 8547605

Title: Band 4.2 Komatsu: 523 GAT-->TAT (175 Asp-->Tyr) in exon 4 of the band 4.2 gene associated with total deficiency of band 4.2, hemolytic anemia with ovalostomatocytosis and marked disruption of the cytoskeletal network.

PubMed ID: 8547605

DOI: 10.1016/0925-5710(95)00372-y

PubMed ID: 10406914

Title: 4.2 Nippon mutation in a non-Japanese patient with hereditary spherocytosis.

PubMed ID: 10406914

Sequence Information:

  • Length: 691
  • Mass: 77009
  • Checksum: 38225C311E478580
  • Sequence:
    • MGQALGIKSC DFQAARNNEE HHTKALSSRR LFVRRGQPFT IILYFRAPVR AFLPALKKVA 
LTAQTGEQPS KINRTQATFP ISSLGDRKWW SAVVEERDAQ SWTISVTTPA DAVIGHYSLL 
LQVSGRKQLL LGQFTLLFNP WNREDAVFLK NEAQRMEYLL NQNGLIYLGT ADCIQAESWD 
FGQFEGDVID LSLRLLSKDK QVEKWSQPVH VARVLGALLH FLKEQRVLPT PQTQATQEGA 
LLNKRRGSVP ILRQWLTGRG RPVYDGQAWV LAAVACTVLR CLGIPARVVT TFASAQGTGG 
RLLIDEYYNE EGLQNGEGQR GRIWIFQTST ECWMTRPALP QGYDGWQILH PSAPNGGGVL 
GSCDLVPVRA VKEGTLGLTP AVSDLFAAIN ASCVVWKCCE DGTLELTDSN TKYVGNNIST 
KGVGSDRCED ITQNYKYPEG SLQEKEVLER VEKEKMEREK DNGIRPPSLE TASPLYLLLK 
APSSLPLRGD AQISVTLVNH SEQEKAVQLA IGVQAVHYNG VLAAKLWRKK LHLTLSANLE 
KIITIGLFFS NFERNPPENT FLRLTAMATH SESNLSCFAQ EDIAICRPHL AIKMPEKAEQ 
YQPLTASVSL QNSLDAPMED CVISILGRGL IHRERSYRFR SVWPENTMCA KFQFTPTHVG 
LQRLTVEVDC NMFQNLTNYK SVTVVAPELS A