Details for: FLG2

Gene ID: 388698

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: FLG2

Ensembl ID: ENSG00000143520

Description: filaggrin 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • basal cell of epidermis CL0002187
    CSI 4.7
    rCSI 8.33%
    PRS 97.46
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 1.71
    rCSI 2.08%
    PRS 98.18

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 [FLG2](/details-gene/388698) encodes Filaggrin-2, a member of the S100 fused-type protein family located within the epidermal differentiation complex on chromosome 1q21.3. This protein is a critical structural component of the epidermis, essential for terminal keratinocyte differentiation and the formation of the skin barrier. Consistent with this, expression data reveals its highest significance in the [basal cell of epidermis](/details-cell/CL0002187). Functionally, [FLG2](/details-gene/388698) is involved in [structural molecule activity](/details-cell/GO:0005198) and [cell adhesion](/details-cell/GO:0007155), and localizes to the [cornified envelope](/details-cell/GO:0001533) and [keratohyalin granules](/details-cell/GO:0036457). Loss-of-function mutations in [FLG2](/details-gene/388698) are known to cause peeling skin syndromes, underscoring its indispensable role in skin integrity ([Link](https://doi.org/10.1016/j.jid.2018.04.032), [Link](https://doi.org/10.1002/ajmg.a.38468)). Emerging data also suggest a potential secondary role within the immune system, supported by its expression in memory T cells and its annotation to pathways such as [Neutrophil degranulation](/details-cell/R-HSA-6798695). ## Cellular Roles and Expression Landscape The expression profile of [FLG2](/details-gene/388698) highlights its primary role as a cornerstone of epidermal biology. **Overall**, the gene shows its most significant expression in [basal cell of epidermis](/details-cell/CL0002187) (CSI: 4.70), the progenitor cells responsible for renewing the epidermis. This high significance is consistent with its established function in keratinocyte differentiation and the multi-step process of forming a protective skin barrier, a process detailed in several studies ([Link](https://doi.org/10.1371/journal.pone.0005227), [Link](https://doi.org/10.1074/jbc.m110.197400)). Its role in maintaining cell-cell adhesion in the cornified layers is critical, as its deficiency leads to dermatological pathologies ([Link](https://doi.org/10.1016/j.jid.2018.04.032)). Interestingly, [FLG2](/details-gene/388698) also demonstrates a notable, albeit lower, significance in [CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203) (CSI: 1.71). This suggests a potential, less-characterized function outside of the skin. This finding is corroborated by its functional annotation to the [Innate immune system](/details-cell/R-HSA-168249) and, more specifically, [Neutrophil degranulation](/details-cell/R-HSA-6798695). The protein's localization to the [tertiary granule lumen](/details-cell/GO:1904724), a compartment within neutrophils, further supports a possible role in the effector functions of immune cells, though its specific contribution in this context remains to be fully elucidated. ## Pathways and Molecular Function The molecular functions of [FLG2](/details-gene/388698) are tightly linked to its structural role in the epidermis and its potential involvement in immune processes. * **Epidermal Morphogenesis and Barrier Function:** The primary biological processes associated with [FLG2](/details-gene/388698) include [Epidermis morphogenesis](/details-cell/GO:0048730) and the [Establishment of skin barrier](/details-cell/GO:0061436). It functions as a structural molecule ([Structural molecule activity](/details-cell/GO:0005198)) and is integral to the [cornified envelope](/details-cell/GO:0001533), the outermost layer of the epidermis that provides a physical barrier against the environment. Its role in [cell adhesion](/details-cell/GO:0007155) is critical for maintaining the cohesion of these layers. The protein's function is also modulated by its ability to bind ions, as indicated by annotations for [calcium ion binding](/details-cell/GO:0005509) and [transition metal ion binding](/details-cell/GO:0046914). * **Immune System Involvement:** Functional annotations place [FLG2](/details-gene/388698) within the broader [Immune system](/details-cell/R-HSA-168256) and more specifically within the [Innate immune system](/details-cell/R-HSA-168249). The association with the [Neutrophil degranulation](/details-cell/R-HSA-6798695) pathway is particularly noteworthy, aligning with its expression in immune cells and its localization to the [tertiary granule lumen](/details-cell/GO:1904724). This suggests that [FLG2](/details-gene/388698) may contribute to the structural organization or release of contents from immune cell granules. ## Research Directions The dual-context expression of [FLG2](/details-gene/388698) in both epidermal and immune cells opens several avenues for future investigation. **Proposed Hypotheses:** 1. **[FLG2](/details-gene/388698) functions as a structural scaffold within the tertiary granules of neutrophils, regulating the proteolytic processing or release of antimicrobial proteins during degranulation.** The absence or dysfunction of [FLG2](/details-gene/388698) could lead to impaired innate immune responses at barrier surfaces like the skin. 2. **In memory T cells, [FLG2](/details-gene/388698) contributes to the structural integrity of the cell cortex or granule-associated membranes, potentially influencing T cell migration, persistence, or cytotoxic effector function.** This could link skin barrier integrity with adaptive immune surveillance. **Experimental Approach:** To test the hypothesis regarding the role of [FLG2](/details-gene/388698) in neutrophil function, the following experiment could be conducted: * **Generate a hematopoietic-specific [FLG2](/details-gene/388698) knockout mouse model (e.g., using a Vav-Cre driver) to avoid embryonic lethality or severe skin defects.** Bone marrow-derived neutrophils would be isolated from knockout and wild-type control mice. The integrity and morphology of tertiary granules could be assessed via transmission electron microscopy. Functional consequences would be measured by stimulating the neutrophils *in vitro* (e.g., with fMLP or PMA) and quantifying the release of tertiary granule markers, such as matrix metalloproteinase-9 (MMP9), using ELISA or zymography. Phagocytic capacity and reactive oxygen species (ROS) production could also be compared to assess overall neutrophil function. **Therapeutic Potential:** Given that known diseases associated with [FLG2](/details-gene/388698) are loss-of-function genetic disorders like peeling skin syndrome, therapeutic strategies would aim to restore its function rather than inhibit it. Therefore, [FLG2](/details-gene/388698) is not a conventional drug target for small molecule inhibition. Instead, it represents a potential candidate for gene replacement therapy or topical protein replacement strategies for patients with severe inherited skin barrier defects. If a significant role in immune dysfunction is confirmed, modulating its expression or function in immune cells could be explored, but this remains a speculative area requiring further foundational research.

Genular Protein ID: 349781976

Symbol: FILA2_HUMAN

Name: Filaggrin-2

UniProtKB Accession Codes:

Q5D862 Q9H4U1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 5 DMDM 1 DNASU 1 DisGeNET 1 EMBL 3 Ensembl 1 GO 12 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRINTS 1 PRO 1 PROSITE 3 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 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 19384417

Title: Molecular identification and expression analysis of filaggrin-2, a member of the S100 fused-type protein family.

PubMed ID: 19384417

DOI: 10.1371/journal.pone.0005227

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21531719

Title: Deimination of human filaggrin-2 promotes its proteolysis by calpain 1.

PubMed ID: 21531719

DOI: 10.1074/jbc.m110.197400

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 28884927

Title: Peeling skin syndrome associated with novel variant in FLG2 gene.

PubMed ID: 28884927

DOI: 10.1002/ajmg.a.38468

PubMed ID: 29758285

Title: Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A.

PubMed ID: 29758285

DOI: 10.1016/j.jid.2018.04.032

PubMed ID: 29505760

Title: Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations.

PubMed ID: 29505760

DOI: 10.1016/j.jid.2018.01.038

PubMed ID: 32341456

Title: De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms.

PubMed ID: 32341456

DOI: 10.1038/s10038-020-0758-2

Sequence Information:

  • Length: 2391
  • Mass: 248073
  • Checksum: 8BC74DE89E0DDC05
  • Sequence:
    • MTDLLRSVVT VIDVFYKYTK QDGECGTLSK GELKELLEKE LHPVLKNPDD PDTVDVIMHM 
LDRDHDRRLD FTEFLLMIFK LTMACNKVLS KEYCKASGSK KHRRGHRHQE EESETEEDEE 
DTPGHKSGYR HSSWSEGEEH GYSSGHSRGT VKCRHGSNSR RLGRQGNLSS SGNQEGSQKR 
YHRSSCGHSW SGGKDRHGSS SVELRERINK SHISPSRESG EEYESGSGSN SWERKGHGGL 
SCGLETSGHE SNSTQSRIRE QKLGSSCSGS GDSGRRSHAC GYSNSSGCGR PQNASSSCQS 
HRFGGQGNQF SYIQSGCQSG IKGGQGHGCV SGGQPSGCGQ PESNPCSQSY SQRGYGAREN 
GQPQNCGGQW RTGSSQSSCC GQYGSGGSQS CSNGQHEYGS CGRFSNSSSS NEFSKCDQYG 
SGSSQSTSFE QHGTGLSQSS GFEQHVCGSG QTCGQHESTS SQSLGYDQHG SSSGKTSGFG 
QHGSGSGQSS GFGQCGSGSG QSSGFGQHGS VSGQSSGFGQ HGSVSGQSSG FGQHESRSRQ 
SSYGQHGSGS SQSSGYGQYG SRETSGFGQH GLGSGQSTGF GQYGSGSGQS SGFGQHGSGS 
GQSSGFGQHE SRSGQSSYGQ HSSGSSQSSG YGQHGSRQTS GFGQHGSGSS QSTGFGQYGS 
GSGQSSGFGQ HVSGSGQSSG FGQHESRSGH SSYGQHGFGS SQSSGYGQHG SSSGQTSGFG 
QHELSSGQSS SFGQHGSGSG QSSGFGQHGS GSGQSSGFGQ HESRSGQSSY GQHSSGSSQS 
SGYGQHGSRQ TSGFGQHGSG SSQSTGFGQY GSGSGQSAGF GQHGSGSGQS SGFGQHESRS 
HQSSYGQHGS GSSQSSGYGQ HGSSSGQTSG FGQHRSSSGQ YSGFGQHGSG SGQSSGFGQH 
GTGSGQYSGF GQHESRSHQS SYGQHGSGSS QSSGYGQHGS SSGQTFGFGQ HRSGSGQSSG 
FGQHGSGSGQ SSGFGQHESG SGKSSGFGQH ESRSSQSNYG QHGSGSSQSS GYGQHGSSSG 
QTTGFGQHRS SSGQYSGFGQ HGSGSDQSSG FGQHGTGSGQ SSGFGQYESR SRQSSYGQHG 
SGSSQSSGYG QHGSNSGQTS GFGQHRPGSG QSSGFGQYGS GSGQSSGFGQ HGSGTGKSSG 
FAQHEYRSGQ SSYGQHGTGS SQSSGCGQHE SGSGPTTSFG QHVSGSDNFS SSGQHISDSG 
QSTGFGQYGS GSGQSTGLGQ GESQQVESGS TVHGRQETTH GQTINTTRHS QSGQGQSTQT 
GSRVTRRRRS SQSENSDSEV HSKVSHRHSE HIHTQAGSHY PKSGSTVRRR QGTTHGQRGD 
TTRHGHSGHG QSTQTGSRTS GRQRFSHSDA TDSEVHSGVS HRPHSQEQTH SQAGSQHGES 
ESTVHERHET TYGQTGEATG HGHSGHGQST QRGSRTTGRR GSGHSESSDS EVHSGGSHRP 
QSQEQTHGQA GSQHGESGST VHGRHGTTHG QTGDTTRHAH YHHGKSTQRG SSTTGRRGSG 
HSESSDSEVH SGGSHTHSGH THGQSGSQHG ESESIIHDRH RITHGQTGDT TRHSYSGHEQ 
TTQTGSRTTG RQRTSHSEST DSEVHSGGSH RPHSREHTYG QAGSQHEEPE FTVHERHGTT 
HGQIGDTTGH SHSGHGQSTQ RGSRTTGRQR SSHSESSDSE VHSGVSHTHT GHTHGQAGSQ 
HGQSESIVPE RHGTTHGQTG DTTRHAHYHH GLTTQTGSRT TGRRGSGHSE YSDSEGYSGV 
SHTHSGHTHG QARSQHGESE SIVHERHGTI HGQTGDTTRH AHSGHGQSTQ TGSRTTGRRS 
SGHSEYSDSE GHSGFSQRPH SRGHTHGQAG SQHGESESIV DERHGTTHGQ TGDTSGHSQS 
GHGQSTQSGS STTGRRRSGH SESSDSEVHS GGSHTHSGHT HSQARSQHGE SESTVHKRHQ 
TTHGQTGDTT EHGHPSHGQT IQTGSRTTGR RGSGHSEYSD SEGPSGVSHT HSGHTHGQAG 
SHYPESGSSV HERHGTTHGQ TADTTRHGHS GHGQSTQRGS RTTGRRASGH SEYSDSEGHS 
GVSHTHSGHA HGQAGSQHGE SGSSVHERHG TTHGQTGDTT RHAHSGHGQS TQRGSRTAGR 
RGSGHSESSD SEVHSGVSHT HSGHTYGQAR SQHGESGSAI HGRQGTIHGQ TGDTTRHGQS 
GHGQSTQTGS RTTGRQRSSH SESSDSEVHS EASPTHSGHT HSQAGSRHGQ SGSSGHGRQG 
TTHGQTGDTT RHAHYGYGQS TQRGSRTTGR RGSGHSESSD SEVHSWGSHT HSGHIQGQAG 
SQQRQPGSTV HGRLETTHGQ TGDTTRHGHS GYGQSTQTGS RSSRASHFQS HSSERQRHGS 
SQVWKHGSYG PAEYDYGHTG YGPSGGSRKS ISNSHLSWST DSTANKQLSR H