Details for: FLG

Gene ID: 2312

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: FLG

Ensembl ID: ENSG00000143631

Description: filaggrin

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • squamous epithelial cell CL0000076
    CSI 3.1
    rCSI 7.35%
    PRS 99.89

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
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    • 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 Analyzed for its specificity (CSI Z-Score), [FLG](/details-gene/2312), or filaggrin, is identified as a quintessential and highly specific structural protein. Its expression is almost exclusively confined to [squamous epithelial cell](/details-cell/CL0000076), where it plays a critical role in terminal differentiation and the formation of the epidermal barrier. This restricted expression pattern underscores its function as a definitive molecular marker for this cell lineage. Loss-of-function mutations in [FLG](/details-gene/2312) are strongly associated with skin barrier defects, predisposing individuals to conditions such as ichthyosis vulgaris and atopic dermatitis. ## Cellular Roles and Expression Landscape The expression profile of [FLG](/details-gene/2312) highlights its role as a highly specialized gene. The analysis, focused on expression specificity, reveals that its activity is overwhelmingly concentrated in [squamous epithelial cell](/details-cell/CL0000076). This is demonstrated by an exceptional percentile rank score (PRS: 99.89%) and a maximal Effect Size (deltaVal: 1.00) in the **Overall** context. These metrics signify that [FLG](/details-gene/2312) expression is not only high but also uniquely restricted to this cell type when compared to all other cells in the dataset. While the provided p-value (0.642) is not statistically significant in this particular analysis, the combination of the maximal effect size and top-tier rank, supported by extensive literature, strongly affirms its status as a canonical marker for epidermal keratinocytes undergoing terminal differentiation. [FLG](/details-gene/2312) is initially synthesized as a large, insoluble polyprotein precursor, profilaggrin, which is stored in keratohyalin granules. During the final stages of keratinocyte differentiation, profilaggrin is dephosphorylated and proteolytically cleaved into functional filaggrin monomers (PubMed: [7612609](https://pubmed.ncbi.nlm.nih.gov/7612609/)). These monomers aggregate keratin intermediate filaments, collapsing the cell's cytoskeleton and contributing to the flattened, anucleated structure of corneocytes that form the stratum corneum. This process is fundamental to the skin's physical resilience and barrier function. ## Pathways and Molecular Function The molecular functions attributed to [FLG](/details-gene/2312) are entirely consistent with its highly specific cellular role. Gene Ontology annotations place it centrally in '[Establishment of skin barrier (GO:0061436)](https://www.ebi.ac.uk/QuickGO/term/GO:0061436)' and '[Keratinocyte differentiation (GO:0030216)](https://www.ebi.ac.uk/QuickGO/term/GO:0030216)'. Its localization to the '[Cornified envelope (GO:0001533)](https://www.ebi.ac.uk/QuickGO/term/GO:0001533)' and '[Keratohyalin granule (GO:0036457)](https://www.ebi.ac.uk/QuickGO/term/GO:0036457)' further defines its role within the specialized machinery of terminally differentiating keratinocytes. Reactome pathway analysis reinforces this, mapping [FLG](/details-gene/2312) to core epidermal processes such as '[Keratinization (R-HSA-6805567)](https://reactome.org/content/detail/R-HSA-6805567)' and '[Formation of the cornified envelope (R-HSA-6809371)](https://reactome.org/content/detail/R-HSA-6809371)'. The disruption of these pathways due to genetic variants explains its strong clinical association with ichthyosis vulgaris ([146700](https://omim.org/entry/146700)), a disorder of cornification (PubMed: [16444271](https://pubmed.ncbi.nlm.nih.gov/16444271/)), and atopic dermatitis ([135940](https://omim.org/entry/135940)), where a compromised barrier allows for increased allergen penetration and sensitization (PubMed: [16550169](https://pubmed.ncbi.nlm.nih.gov/16550169/)). ## Research Directions The highly specific expression and critical function of [FLG](/details-gene/2312) in skin barrier integrity make it a key target for dermatological research. Future studies should focus on the regulatory mechanisms governing its expression and the functional consequences of its post-translational modifications. **Testable Hypotheses:** 1. **Hypothesis:** Inflammatory cytokines associated with atopic dermatitis, such as IL-4 and IL-13, suppress [FLG](/details-gene/2312) expression not only at the transcriptional level but also by altering the activity of proteases responsible for processing profilaggrin, leading to an accumulation of unprocessed precursor and a functionally impaired epidermal barrier even in patients without [FLG](/details-gene/2312) null mutations. * **Experimental Approach:** Utilize 3D human skin equivalents or primary keratinocyte cultures. Treat with IL-4/IL-13 and perform quantitative PCR for [FLG](/details-gene/2312) mRNA, alongside Western blotting with antibodies specific to profilaggrin and cleaved filaggrin to assess processing efficiency. 2. **Hypothesis:** The microbiome of the skin directly modulates [FLG](/details-gene/2312) expression. Specific bacterial species, such as *Staphylococcus aureus*, which often colonize atopic skin, may produce metabolites or proteases that actively degrade filaggrin or suppress its gene expression, thereby exacerbating barrier dysfunction. * **Experimental Approach:** Co-culture primary human keratinocytes with live *S. aureus* or its secreted products. Measure [FLG](/details-gene/2312) mRNA levels and protein expression. Mass spectrometry could be used to identify filaggrin degradation products specific to bacterial exposure. 3. **Hypothesis:** Filaggrin-derived breakdown products, known as natural moisturizing factors (NMFs), which are critical for skin hydration, may also have signaling roles beyond the epidermis. It is hypothesized that reduced NMF levels in the skin of individuals with [FLG](/details-gene/2312) mutations lead to altered local immune cell function, promoting a pro-inflammatory T-helper 2 (Th2) phenotype in resident T cells. * **Experimental Approach:** Isolate resident memory T cells from skin biopsies of healthy controls and patients with known [FLG](/details-gene/2312) mutations. Culture these T cells in media supplemented with or depleted of key NMF components (e.g., urocanic acid, pyrrolidone carboxylic acid) and assess their cytokine production profiles (e.g., IL-4, IFN-gamma) via flow cytometry or ELISA. **Therapeutic Potential:** Given that [FLG](/details-gene/2312) encodes a structural protein, therapeutic strategies are unlikely to target it directly. Instead, focus should be on modulating its expression and function. The development of small molecules that can upregulate [FLG](/details-gene/2312) transcription by targeting its regulatory pathways represents a promising avenue for treating barrier-deficient diseases. Furthermore, advanced topical formulations designed to deliver NMFs or other compounds that can functionally compensate for filaggrin deficiency remain a cornerstone of therapy and an area for continued innovation.

Genular Protein ID: 2686266898

Symbol: FILA_HUMAN

Name: Filaggrin

UniProtKB Accession Codes:

P20930 Q01720 Q5T583 Q9UC71

Database IDs:

AGR 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 5 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 3 Ensembl 1 EvolutionaryTrace 1 GO 12 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 3 PRIDE 1 PRINTS 1 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TopDownProteomics 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 16710414

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

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 1429717

Title: Characterization of the human epidermal profilaggrin gene. Genomic organization and identification of an S-100-like calcium binding domain at the amino terminus.

PubMed ID: 1429717

DOI: 10.1016/s0021-9258(18)35905-2

PubMed ID: 2740331

Title: Characterization of a cDNA clone encoding human filaggrin and localization of the gene to chromosome region 1q21.

PubMed ID: 2740331

DOI: 10.1073/pnas.86.13.4848

PubMed ID: 7612609

Title: Identification of the amino terminus of human filaggrin using differential LC/MS techniques: implications for profilaggrin processing.

PubMed ID: 7612609

DOI: 10.1021/bi00027a018

PubMed ID: 25946035

Title: Human basal tear peptidome characterization by CID, HCD, and ETD followed by in silico and in vitro analyses for antimicrobial peptide identification.

PubMed ID: 25946035

DOI: 10.1021/acs.jproteome.5b00179

PubMed ID: 8780679

Title: Preferential deimination of keratin K1 and filaggrin during the terminal differentiation of human epidermis.

PubMed ID: 8780679

DOI: 10.1006/bbrc.1996.1240

PubMed ID: 16815158

Title: Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations.

PubMed ID: 16815158

DOI: 10.1016/j.jaci.2006.05.004

PubMed ID: 17030239

Title: Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march.

PubMed ID: 17030239

DOI: 10.1016/j.jaci.2006.07.026

PubMed ID: 16444271

Title: Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.

PubMed ID: 16444271

DOI: 10.1038/ng1743

PubMed ID: 16550169

Title: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

PubMed ID: 16550169

DOI: 10.1038/ng1767

PubMed ID: 17291859

Title: Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis.

PubMed ID: 17291859

DOI: 10.1016/j.jaci.2006.12.646

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: 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

Sequence Information:

  • Length: 4061
  • Mass: 435170
  • Checksum: 3F4B1181F04AD9C0
  • Sequence:
    • MSTLLENIFA IINLFKQYSK KDKNTDTLSK KELKELLEKE FRQILKNPDD PDMVDVFMDH 
LDIDHNKKID FTEFLLMVFK LAQAYYESTR KENLPISGHK HRKHSHHDKH EDNKQEENKE 
NRKRPSSLER RNNRKGNKGR SKSPRETGGK RHESSSEKKE RKGYSPTHRE EEYGKNHHNS 
SKKEKNKTEN TRLGDNRKRL SERLEEKEDN EEGVYDYENT GRMTQKWIQS GHIATYYTIQ 
DEAYDTTDSL LEENKIYERS RSSDGKSSSQ VNRSRHENTS QVPLQESRTR KRRGSRVSQD 
RDSEGHSEDS ERHSGSASRN HHGSAWEQSR DGSRHPRSHD EDRASHGHSA DSSRQSGTRH 
AETSSRGQTA SSHEQARSSP GERHGSGHQQ SADSSRHSAT GRGQASSAVS DRGHRGSSGS 
QASDSEGHSE NSDTQSVSGH GKAGLRQQSH QESTRGRSGE RSGRSGSSLY QVSTHEQPDS 
AHGRTGTSTG GRQGSHHEQA RDSSRHSASQ EGQDTIRGHP GSSRGGRQGS HHEQSVNRSG 
HSGSHHSHTT SQGRSDASHG QSGSRSASRQ TRNEEQSGDG TRHSGSRHHE ASSQADSSRH 
SQVGQGQSSG PRTSRNQGSS VSQDSDSQGH SEDSERWSGS ASRNHHGSAQ EQSRDGSRHP 
RSHHEDRAGH GHSADSSRKS GTRHTQNSSS GQAASSHEQA RSSAGERHGS RHQLQSADSS 
RHSGTGHGQA SSAVRDSGHR GSSGSQATDS EGHSEDSDTQ SVSGHGQAGH HQQSHQESAR 
DRSGERSRRS GSFLYQVSTH KQSESSHGWT GPSTGVRQGS HHEQARDNSR HSASQDGQDT 
IRGHPGSSRR GRQGSHHEQS VDRSGHSGSH HSHTTSQGRS DASRGQSGSR SASRTTRNEE 
QSRDGSRHSG SRHHEASSHA DISRHSQAGQ GQSEGSRTSR RQGSSVSQDS DSEGHSEDSE 
RWSGSASRNH RGSAQEQSRH GSRHPRSHHE DRAGHGHSAD SSRQSGTPHA ETSSGGQAAS 
SHEQARSSPG ERHGSRHQQS ADSSRHSGIP RRQASSAVRD SGHWGSSGSQ ASDSEGHSEE 
SDTQSVSGHG QDGPHQQSHQ ESARDWSGGR SGRSGSFIYQ VSTHEQSESA HGRTRTSTGR 
RQGSHHEQAR DSSRHSASQE GQDTIRAHPG SRRGGRQGSH HEQSVDRSGH SGSHHSHTTS 
QGRSDASHGQ SGSRSASRQT RKDKQSGDGS RHSGSRHHEA ASWADSSRHS QVGQEQSSGS 
RTSRHQGSSV SQDSDSERHS DDSERLSGSA SRNHHGSSRE QSRDGSRHPG FHQEDRASHG 
HSADSSRQSG THHTESSSHG QAVSSHEQAR SSPGERHGSR HQQSADSSRH SGIGHRQASS 
AVRDSGHRGS SGSQVTNSEG HSEDSDTQSV SAHGQAGPHQ QSHKESARGQ SGESSGRSRS 
FLYQVSSHEQ SESTHGQTAP STGGRQGSRH EQARNSSRHS ASQDGQDTIR GHPGSSRGGR 
QGSYHEQSVD RSGHSGYHHS HTTPQGRSDA SHGQSGPRSA SRQTRNEEQS GDGSRHSGSR 
HHEPSTRAGS SRHSQVGQGE SAGSKTSRRQ GSSVSQDRDS EGHSEDSERR SESASRNHYG 
SAREQSRHGS RNPRSHQEDR ASHGHSAESS RQSGTRHAET SSGGQAASSQ EQARSSPGER 
HGSRHQQSAD SSTDSGTGRR QDSSVVGDSG NRGSSGSQAS DSEGHSEESD TQSVSAHGQA 
GPHQQSHQES TRGQSGERSG RSGSFLYQVS THEQSESAHG RTGPSTGGRQ RSRHEQARDS 
SRHSASQEGQ DTIRGHPGSS RGGRQGSHYE QSVDSSGHSG SHHSHTTSQE RSDVSRGQSG 
SRSVSRQTRN EKQSGDGSRH SGSRHHEASS RADSSRHSQV GQGQSSGPRT SRNQGSSVSQ 
DSDSQGHSED SERWSGSASR NHLGSAWEQS RDGSRHPGSH HEDRAGHGHS ADSSRQSGTR 
HTESSSRGQA ASSHEQARSS AGERHGSHHQ LQSADSSRHS GIGHGQASSA VRDSGHRGYS 
GSQASDSEGH SEDSDTQSVS AQGKAGPHQQ SHKESARGQS GESSGRSGSF LYQVSTHEQS 
ESTHGQSAPS TGGRQGSHYD QAQDSSRHSA SQEGQDTIRG HPGPSRGGRQ GSHQEQSVDR 
SGHSGSHHSH TTSQGRSDAS RGQSGSRSAS RKTYDKEQSG DGSRHSGSHH HEASSWADSS 
RHSLVGQGQS SGPRTSRPRG SSVSQDSDSE GHSEDSERRS GSASRNHHGS AQEQSRDGSR 
HPRSHHEDRA GHGHSAESSR QSGTHHAENS SGGQAASSHE QARSSAGERH GSHHQQSADS 
SRHSGIGHGQ ASSAVRDSGH RGSSGSQASD SEGHSEDSDT QSVSAHGQAG PHQQSHQEST 
RGRSAGRSGR SGSFLYQVST HEQSESAHGR TGTSTGGRQG SHHKQARDSS RHSTSQEGQD 
TIHGHPGSSS GGRQGSHYEQ LVDRSGHSGS HHSHTTSQGR SDASHGHSGS RSASRQTRND 
EQSGDGSRHS GSRHHEASSR ADSSGHSQVG QGQSEGPRTS RNWGSSFSQD SDSQGHSEDS 
ERWSGSASRN HHGSAQEQLR DGSRHPRSHQ EDRAGHGHSA DSSRQSGTRH TQTSSGGQAA 
SSHEQARSSA GERHGSHHQQ SADSSRHSGI GHGQASSAVR DSGHRGYSGS QASDNEGHSE 
DSDTQSVSAH GQAGSHQQSH QESARGRSGE TSGHSGSFLY QVSTHEQSES SHGWTGPSTR 
GRQGSRHEQA QDSSRHSASQ DGQDTIRGHP GSSRGGRQGY HHEHSVDSSG HSGSHHSHTT 
SQGRSDASRG QSGSRSASRT TRNEEQSGDG SRHSGSRHHE ASTHADISRH SQAVQGQSEG 
SRRSRRQGSS VSQDSDSEGH SEDSERWSGS ASRNHHGSAQ EQLRDGSRHP RSHQEDRAGH 
GHSADSSRQS GTRHTQTSSG GQAASSHEQA RSSAGERHGS HHQQSADSSR HSGIGHGQAS 
SAVRDSGHRG YSGSQASDNE GHSEDSDTQS VSAHGQAGSH QQSHQESARG RSGETSGHSG 
SFLYQVSTHE QSESSHGWTG PSTRGRQGSR HEQAQDSSRH SASQYGQDTI RGHPGSSRGG 
RQGYHHEHSV DSSGHSGSHH SHTTSQGRSD ASRGQSGSRS ASRTTRNEEQ SGDSSRHSVS 
RHHEASTHAD ISRHSQAVQG QSEGSRRSRR QGSSVSQDSD SEGHSEDSER WSGSASRNHR 
GSVQEQSRHG SRHPRSHHED RAGHGHSADR SRQSGTRHAE TSSGGQAASS HEQARSSPGE 
RHGSRHQQSA DSSRHSGIPR GQASSAVRDS RHWGSSGSQA SDSEGHSEES DTQSVSGHGQ 
AGPHQQSHQE SARDRSGGRS GRSGSFLYQV STHEQSESAH GRTRTSTGRR QGSHHEQARD 
SSRHSASQEG QDTIRGHPGS SRRGRQGSHY EQSVDRSGHS GSHHSHTTSQ GRSDASRGQS 
GSRSASRQTR NDEQSGDGSR HSWSHHHEAS TQADSSRHSQ SGQGQSAGPR TSRNQGSSVS 
QDSDSQGHSE DSERWSGSAS RNHRGSAQEQ SRDGSRHPTS HHEDRAGHGH SAESSRQSGT 
HHAENSSGGQ AASSHEQARS SAGERHGSHH QQSADSSRHS GIGHGQASSA VRDSGHRGSS 
GSQASDSEGH SEDSDTQSVS AHGQAGPHQQ SHQESTRGRS AGRSGRSGSF LYQVSTHEQS 
ESAHGRAGPS TGGRQGSRHE QARDSSRHSA SQEGQDTIRG HPGSRRGGRQ GSYHEQSVDR 
SGHSGSHHSH TTSQGRSDAS HGQSGSRSAS RETRNEEQSG DGSRHSGSRH HEASTQADSS 
RHSQSGQGES AGSRRSRRQG SSVSQDSDSE AYPEDSERRS ESASRNHHGS SREQSRDGSR 
HPGSSHRDTA SHVQSSPVQS DSSTAKEHGH FSSLSQDSAY HSGIQSRGSP HSSSSYHYQS 
EGTERQKGQS GLVWRHGSYG SADYDYGESG FRHSQHGSVS YNSNPVVFKE RSDICKASAF 
GKDHPRYYAT YINKDPGLCG HSSDISKQLG FSQSQRYYYY E