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Gene Review

FLG  -  filaggrin

Homo sapiens

Synonyms: Filaggrin
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Disease relevance of FLG


High impact information on FLG


Chemical compound and disease context of FLG


Biological context of FLG


Anatomical context of FLG

  • Filaggrin was first detected biochemically at approximately 15 wk and was localized immunohistochemically in the keratinizing cells that surround hair follicles [20].
  • The cytoplasmic surface of intact purified CEs consists of filaggrin, loricrin, SPRs and keratin intermediate filaments [21].
  • Regulated expression of human filaggrin in keratinocytes results in cytoskeletal disruption, loss of cell-cell adhesion, and cell cycle arrest [17].
  • These studies demonstrate that filaggrin, in addition to its known effects on IF organization, can affect the distribution of other cytoskeletal elements including actin microfilaments, which can occur in the absence of a cytoplasmic IF network [17].
  • Further, filaggrin can disrupt the distribution of desmosome proteins, suggesting an additional role(s) for this protein in the cytoskeletal and desmosomal reorganization that occurs at the granular to cornified cell transition during terminal differentiation of epidermal keratinocytes [17].

Associations of FLG with chemical compounds

  • These results indicate that citrulline residues are constitutive of the AFA epitopes, but only in the context of specific amino acid sequences of filaggrin [22].
  • Using casein kinase II phosphorylated filaggrin as substrate, a profilaggrin phosphatase has been partially purified from rat epidermal homogenate by three chromatographic steps (DE52, hydroxylapatite and S200 gel filtration) [23].
  • In contrast, extracts of epidermis from retinoid-treated skin contained additional keratins (K6, K16, and K17) and almost no detectable filaggrin [24].
  • The findings that topical RA decreased filaggrin expression and reduced proteolysis of stratum corneum keratins, despite increased size and number of granular cells and the presence of an anucleate stratum corneum, suggest that topical RA may also modulate a later stage of epidermal differentiation involved in stratum corneum formation [24].
  • Filaggrin was present on stained sodium dodecyl sulfate gels and immunoblots of epidermal proteins from controls and unaffected family members [25].

Physical interactions of FLG


Regulatory relationships of FLG


Other interactions of FLG

  • Filaggrin is an intermediate filament (IF)-associated protein that aggregates keratin IFs in vitro and is thought to perform a similar function during the terminal differentiation of epidermal keratinocytes [17].
  • Moreover, two of three filaggrin-derived synthetic peptides with a citrulline in the central position were specifically and widely recognized by AFA affinity-purified from a series of RA sera [22].
  • For keratins, transglutaminase, loricrin and filaggrin colocalization was found in more than 60% of the samples [30].
  • Some buccal samples showed an alternate staining pattern of spotty suprabasal staining with AE1 and AE2 which was correlated with the expression of the 56.5K and 63-67K keratins, as well as filaggrin [31].
  • EGF also depressed several indicators of differentiation: The number of keratohyalin granules and membrane-coating granules was greatly decreased; antigen expression of profilaggrin/filaggrin appeared diminished by immunocytochemical staining; frequent nuclear retention was noted in the relatively thickened stratum corneum-like layers [32].

Analytical, diagnostic and therapeutic context of FLG


  1. Cutaneous dermoid cyst: cytokeratin and filaggrin expression suggesting differentiation towards follicular infundibulum and mature sebaceous gland. Kurokawa, I., Nishimura, K., Hakamada, A., Isoda, K., Yamanaka, K., Mizutani, H., Tsubura, A. Oncol. Rep. (2006) [Pubmed]
  2. Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome. Hewett, D.R., Simons, A.L., Mangan, N.E., Jolin, H.E., Green, S.M., Fallon, P.G., McKenzie, A.N. Hum. Mol. Genet. (2005) [Pubmed]
  3. Activated keratinocytes in the epidermis of hypertrophic scars. Machesney, M., Tidman, N., Waseem, A., Kirby, L., Leigh, I. Am. J. Pathol. (1998) [Pubmed]
  4. Filaggrin expression in epidermolytic ichthyosis (epidermolytic hyperkeratosis). Ishida-Yamamoto, A., Eady, R.A., Underwood, R.A., Dale, B.A., Holbrook, K.A. Br. J. Dermatol. (1994) [Pubmed]
  5. High levels of cytokeratin 19 fragments but no evidence of cytokeratins 1, 2, 10/11, 14 or filaggrin in the serum of squamous cell lung carcinoma patients. Miédougé, M., Devys, A., Simon, M., Rouzaud, P., Salama, G., Reyre, J., Pujazon, M., Carles, P., Serre, G. Tumour Biol. (2001) [Pubmed]
  6. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Sandilands, A., Terron-Kwiatkowski, A., Hull, P.R., O'Regan, G.M., Clayton, T.H., Watson, R.M., Carrick, T., Evans, A.T., Liao, H., Zhao, Y., Campbell, L.E., Schmuth, M., Gruber, R., Janecke, A.R., Elias, P.M., van Steensel, M.A., Nagtzaam, I., van Geel, M., Steijlen, P.M., Munro, C.S., Bradley, D.G., Palmer, C.N., Smith, F.J., McLean, W.H., Irvine, A.D. Nat. Genet. (2007) [Pubmed]
  7. Filaggrin null mutations are associated with increased asthma severity in children and young adults. Palmer, C.N., Ismail, T., Lee, S.P., Terron-Kwiatkowski, A., Zhao, Y., Liao, H., Smith, F.J., McLean, W.H., Mukhopadhyay, S. J. Allergy Clin. Immunol. (2007) [Pubmed]
  8. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Smith, F.J., Irvine, A.D., Terron-Kwiatkowski, A., Sandilands, A., Campbell, L.E., Zhao, Y., Liao, H., Evans, A.T., Goudie, D.R., Lewis-Jones, S., Arseculeratne, G., Munro, C.S., Sergeant, A., O'Regan, G., Bale, S.J., Compton, J.G., DiGiovanna, J.J., Presland, R.B., Fleckman, P., McLean, W.H. Nat. Genet. (2006) [Pubmed]
  9. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Palmer, C.N., Irvine, A.D., Terron-Kwiatkowski, A., Zhao, Y., Liao, H., Lee, S.P., Goudie, D.R., Sandilands, A., Campbell, L.E., Smith, F.J., O'regan, G.M., Watson, R.M., Cecil, J.E., Bale, S.J., Compton, J.G., Digiovanna, J.J., Fleckman, P., Lewis-Jones, S., Arseculeratne, G., Sergeant, A., Munro, C.S., El Houate, B., McElreavey, K., Halkjaer, L.B., Bisgaard, H., Mukhopadhyay, S., McLean, W.H. Nat. Genet. (2006) [Pubmed]
  10. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. Sebbag, M., Simon, M., Vincent, C., Masson-Bessière, C., Girbal, E., Durieux, J.J., Serre, G. J. Clin. Invest. (1995) [Pubmed]
  11. Comparison of cytokeratin, filaggrin and involucrin profiles in oral leukoplakias and squamous carcinomas. Vigneswaran, N., Peters, K.P., Hornstein, O.P., Haneke, E. J. Oral Pathol. Med. (1989) [Pubmed]
  12. Restoration of the epidermal phenotype by follicular outer root sheath cells in recombinant culture with dermal fibroblasts. Limat, A., Breitkreutz, D., Hunziker, T., Boillat, C., Wiesmann, U., Klein, E., Noser, F., Fusenig, N.E. Exp. Cell Res. (1991) [Pubmed]
  13. Expression of epidermal N-methyl-D-aspartate receptors (NMDAR1) depends on formation of the granular layer--analysis in diseases with parakeratotic cornification. Fischer, M., William, T., Helmbold, P., Wohlrab, J., Marsch, W.C.h. Arch. Dermatol. Res. (2004) [Pubmed]
  14. Alteration of epidermal differentiation in middle ear cholesteatoma. Stammberger, M., Bujía, J., Kastenbauer, E. The American journal of otology. (1995) [Pubmed]
  15. Stratum corneum pH in atopic dermatitis: impact on skin barrier function and colonization with Staphylococcus Aureus. Rippke, F., Schreiner, V., Doering, T., Maibach, H.I. American journal of clinical dermatology. (2004) [Pubmed]
  16. Characterization of the human epidermal profilaggrin gene. Genomic organization and identification of an S-100-like calcium binding domain at the amino terminus. Presland, R.B., Haydock, P.V., Fleckman, P., Nirunsuksiri, W., Dale, B.A. J. Biol. Chem. (1992) [Pubmed]
  17. Regulated expression of human filaggrin in keratinocytes results in cytoskeletal disruption, loss of cell-cell adhesion, and cell cycle arrest. Presland, R.B., Kuechle, M.K., Lewis, S.P., Fleckman, P., Dale, B.A. Exp. Cell Res. (2001) [Pubmed]
  18. Cytokeratin, filaggrin, and p63 expression in reepithelialization during human cutaneous wound healing. Kurokawa, I., Mizutani, H., Kusumoto, K., Nishijima, S., Tsujita-Kyutoku, M., Shikata, N., Tsubura, A. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. (2006) [Pubmed]
  19. Regulation of calprotectin expression by interleukin-1alpha and transforming growth factor-beta in human gingival keratinocytes. Hayashi, N., Kido, J., Kido, R., Wada, C., Kataoka, M., Shinohara, Y., Nagata, T. J. Periodont. Res. (2007) [Pubmed]
  20. Expression of epidermal keratins and filaggrin during human fetal skin development. Dale, B.A., Holbrook, K.A., Kimball, J.R., Hoff, M., Sun, T.T. J. Cell Biol. (1985) [Pubmed]
  21. A model for the hierarchical structure of the human epidermal cornified cell envelope. Steinert, P.M. Cell Death Differ. (1995) [Pubmed]
  22. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. Girbal-Neuhauser, E., Durieux, J.J., Arnaud, M., Dalbon, P., Sebbag, M., Vincent, C., Simon, M., Senshu, T., Masson-Bessière, C., Jolivet-Reynaud, C., Jolivet, M., Serre, G. J. Immunol. (1999) [Pubmed]
  23. Identification of rat epidermal profilaggrin phosphatase as a member of the protein phosphatase 2A family. Kam, E., Resing, K.A., Lim, S.K., Dale, B.A. J. Cell. Sci. (1993) [Pubmed]
  24. Effects of topical retinoids on cytoskeletal proteins: implications for retinoid effects on epidermal differentiation. Eichner, R., Kahn, M., Capetola, R.J., Gendimenico, G.J., Mezick, J.A. J. Invest. Dermatol. (1992) [Pubmed]
  25. Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules. Sybert, V.P., Dale, B.A., Holbrook, K.A. J. Invest. Dermatol. (1985) [Pubmed]
  26. Profilaggrin requires both linker and filaggrin peptide sequences to form granules: implications for profilaggrin processing in vivo. Kuechle, M.K., Thulin, C.D., Presland, R.B., Dale, B.A. J. Invest. Dermatol. (1999) [Pubmed]
  27. Clinical significance of anti-filaggrin antibody recognizing uncitrullinated filaggrin in rheumatoid arthritis. Choi, K.H., Lee, E.B., Yoo, C.D., Baek, H.J., Kang, S.W., Shin, K.C., Lee, Y.J., Kim, H.A., Jeon, J.H., Kim, C.W., Shin, D.M., Kim, I.G., Son, Y.W. Exp. Mol. Med. (2005) [Pubmed]
  28. Transcription of the human loricrin gene in vitro is induced by calcium and cell density and suppressed by retinoic acid. Hohl, D., Lichti, U., Breitkreutz, D., Steinert, P.M., Roop, D.R. J. Invest. Dermatol. (1991) [Pubmed]
  29. Differential patterns of filaggrin expression in lamellar ichthyosis. Peña Penabad, C., Pérez Arellano, J.L., Becker, E., Gutierrez de Diego, J., García Salgado, M.J., Valle, F.J., Unamuno Pérez, P. Br. J. Dermatol. (1998) [Pubmed]
  30. Subcorneal colocalization of the small heat shock protein, hsp27, with keratins and proteins of the cornified cell envelope. Jonak, C., Klosner, G., Kokesch, C., FOdinger, D., HOnigsmann, H., Trautinger, F. Br. J. Dermatol. (2002) [Pubmed]
  31. Differentiation-dependent expression of keratins in human oral epithelia. Clausen, H., Vedtofte, P., Moe, D., Dabelsteen, E., Sun, T.T., Dale, B. J. Invest. Dermatol. (1986) [Pubmed]
  32. Use of a serum-free epidermal culture model to show deleterious effects of epidermal growth factor on morphogenesis and differentiation. Chen, C.S., Lavker, R.M., Rodeck, U., Risse, B., Jensen, P.J. J. Invest. Dermatol. (1995) [Pubmed]
  33. Characterization of a cDNA clone encoding human filaggrin and localization of the gene to chromosome region 1q21. McKinley-Grant, L.J., Idler, W.W., Bernstein, I.A., Parry, D.A., Cannizzaro, L., Croce, C.M., Huebner, K., Lessin, S.R., Steinert, P.M. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  34. The peptidylarginine deiminases expressed in human epidermis differ in their substrate specificities and subcellular locations. Méchin, M.C., Enji, M., Nachat, R., Chavanas, S., Charveron, M., Ishida-Yamamoto, A., Serre, G., Takahara, H., Simon, M. Cell. Mol. Life Sci. (2005) [Pubmed]
  35. Vitamin C enhances differentiation of a continuous keratinocyte cell line (REK) into epidermis with normal stratum corneum ultrastructure and functional permeability barrier. Pasonen-Seppänen, S., Suhonen, T.M., Kirjavainen, M., Suihko, E., Urtti, A., Miettinen, M., Hyttinen, M., Tammi, M., Tammi, R. Histochem. Cell Biol. (2001) [Pubmed]
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