Filaggrin

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Filaggrin
Identifiers
Symbols FLG ; ATOD2
External IDs OMIM135940 HomoloGene84700 GeneCards: FLG Gene
Orthologs
Species Human Mouse
Entrez 2312 14246
Ensembl ENSG00000143631 ENSMUSG00000091340
UniProt P20930 P11088
RefSeq (mRNA) NM_002016 XM_485270.6
RefSeq (protein) NP_002007 XP_485270.6
Location (UCSC) Chr 1:
152.27 – 152.3 Mb
Chr 3:
93.08 – 93.08 Mb
PubMed search [1] [2]

Filaggrin is a filament-associated protein that binds to keratin fibers in epithelial cells.

Profilaggrin[edit]

Filaggrin monomers are tandemly clustered into a large, 350kDa protein precursor known as profilaggrin. In the epidermis, these structures are present in the keratohyalin granules in cells of the stratum granulosum. Profilaggrin undergoes proteolytic processing to yield individual filaggrin monomers at the transition between the stratum granulosum and the stratum corneum, which may be facilitated by calcium-dependant enzymes.[1]

Function[edit]

Filaggrin is essential for the regulation of epidermal homeostasis. Within the stratum corneum, filaggrin monomers can become incorporated into the lipid envelope, which is responsible for the skin barrier function. Alternatively, these proteins can interact with keratin intermediate filaments. Filaggrin undergoes further processing in the upper stratum corneum to release free amino acids that assist in water retention.[1]

Clinical significance[edit]

Individuals with truncation mutations in the gene coding for filaggrin are strongly predisposed to a severe form of dry skin, ichthyosis vulgaris, and/or eczema.[2]

Scientists hope to develop treatments for eczema through their newfound knowledge of filaggrin.

Truncation mutations R501X and 2284del4 are the most common mutations in the Caucasian population, with 7 to 10% of the Caucasian population carrying at least one copy of these mutations.[3]

It has been shown that almost 50% of all severe cases of eczema may have at least one mutated filaggrin gene.

R501X and 2284del4 are not generally found in non-Caucasian individuals, though novel mutations (3321delA and S2554X) that yield similar effects have been found in Japanese populations.[4]

Autoantibodies in rheumatoid arthritis recognizing an epitope of citrullinated peptides are cross-reactive with filaggrin.[5]

The barrier defect seen in filaggrin null carriers also appears to lead to increased asthma susceptibility and exacerbations.[6][7][8]

Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression.[9]

The penetrance of filaggrin mutations may be increased by household exposure to cats.[10]

See also[edit]

References[edit]

  1. ^ a b Ovaere P, Lippens S, Vandenabeele P, Declercq W; Lippens; Vandenabeele; Declercq (September 2009). "The emerging roles of serine protease cascades in the epidermis". Trends Biochem. Sci. 34 (9): 453–63. doi:10.1016/j.tibs.2009.08.001. PMID 19726197. 
  2. ^ Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, Klopp N, Wagenpfeil S, Zhao Y, Liao H, Lee SP, Palmer CN, Jenneck C, Maintz L, Hagemann T, Behrendt H, Ring J, Nothen MM, McLean WH, Novak N; Illig; Baurecht; Irvine; Rodriguez; Diaz-Lacava; Klopp; Wagenpfeil; Zhao; Liao; Lee; Palmer; Jenneck; Maintz; Hagemann; Behrendt; Ring; Nothen; McLean; Novak (July 2006). "Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations". J. Allergy Clin. Immunol. 118 (1): 214–9. doi:10.1016/j.jaci.2006.05.004. PMID 16815158. 
  3. ^ Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH; Irvine; Terron-Kwiatkowski; Zhao; Liao; Lee; Goudie; Sandilands; Campbell; Smith; O'Regan; Watson; Cecil; Bale; Compton; Digiovanna; Fleckman; Lewis-Jones; Arseculeratne; Sergeant; Munro; El Houate; McElreavey; Halkjaer; Bisgaard; Mukhopadhyay; McLean (April 2006). "Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis". Nat. Genet. 38 (4): 441–6. doi:10.1038/ng1767. PMID 16550169. 
  4. ^ Nomura T, Sandilands A, Akiyama M, Liao H, Evans AT, Sakai K, Ota M, Sugiura H, Yamamoto K, Sato H, Palmer CN, Smith FJ, McLean WH, Shimizu H; Sandilands; Akiyama; Liao; Evans; Sakai; Ota; Sugiura; Yamamoto; Sato; Palmer; Smith; McLean; Shimizu (February 2007). "Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis". J. Allergy Clin. Immunol. 119 (2): 434–40. doi:10.1016/j.jaci.2006.12.646. PMID 17291859. 
  5. ^ Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ; De Jong; Van Den Hoogen; Van De Putte; Van Venrooij (January 1998). "Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies". J. Clin. Invest. 101 (1): 273–81. doi:10.1172/JCI1316. PMC 508564. PMID 9421490. 
  6. ^ Basu K, K, Palmer, C. N., Lipworth, B. J., Irwin Mclean, Terron-Kwiatkowski, Zhao, Liao, Smith, Mitra, Mukhopadhyay (2008). "Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults". Allergy 63 (9): 1211–7. doi:10.1111/j.1398-9995.2008.01660.x. PMID 18307574. 
  7. ^ Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, McLean WH, Mukhopadhyay S; Ismail; Lee; Terron-Kwiatkowski; Zhao; Liao; Smith; McLean; Mukhopadhyay (July 2007). "Filaggrin null mutations are associated with increased asthma severity in children and young adults". J. Allergy Clin. Immunol. 120 (1): 64–8. doi:10.1016/j.jaci.2007.04.001. PMID 17531295. 
  8. ^ Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, Mukhopadhyay S, Smith GD, Palmer CN, McLean WH, Irvine AD; Northstone; Lee; Liao; Zhao; Pembrey; Mukhopadhyay; Smith; Palmer; McLean; Irvine (April 2008). "The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study". J. Allergy Clin. Immunol. 121 (4): 872–7.e9. doi:10.1016/j.jaci.2008.01.026. PMID 18325573. 
  9. ^ Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN; MacGregor; Mukhopadhyay; Palmer (April 2008). "A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications". J. Allergy Clin. Immunol. 121 (4): 860–3. doi:10.1016/j.jaci.2008.01.015. PMID 18395550. 
  10. ^ Bisgaard H, Simpson A, Palmer CN, Bønnelykke K, McLean I, Mukhopadhyay S, Pipper CB, Halkjaer LB, Lipworth B, Hankinson J, Woodcock A, Custovic A; Simpson; Palmer; Bønnelykke; McLean; Mukhopadhyay; Pipper; Halkjaer; Lipworth; Hankinson; Woodcock; Custovic (June 2008). "Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure". PLoS Med. 5 (6): e131. doi:10.1371/journal.pmed.0050131. PMC 2504043. PMID 18578563. 

External links[edit]