WordNet

the main protein of the keratohyalin granules; "the specific target of the immune response in rheumatoid arthritis is filaggrin"

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/04/11 20:06:35」(JST)

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

Profilaggrin

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

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

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 7-10% 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) have been found in Japanese populations that yield similar effects.^[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]

References

^ ^a ^b Ovaere P, Lippens S, Vandenabeele P, Declercq W (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.
^ 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 (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.
^ 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 (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.
^ 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 (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.
^ Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ (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.
^ Basu K, Palmer CN, Lipworth BJ, Irwin McLean WH, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, Mitra A, Mukhopadhyay S (September 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.
^ Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, McLean WH, Mukhopadhyay S (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.
^ Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, Mukhopadhyay S, Smith GD, Palmer CN, McLean WH, Irvine AD (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.
^ Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN (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.
^ Bisgaard H, Simpson A, Palmer CN, Bønnelykke K, McLean I, Mukhopadhyay S, Pipper CB, Halkjaer LB, Lipworth B, Hankinson J, Woodcock A, Custovic A (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

Filaggrin at the US National Library of Medicine Medical Subject Headings (MeSH)

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UpToDate Contents

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1. アトピー性皮膚炎（湿疹）の疫学、臨床症状、および診断 epidemiology clinical manifestations and diagnosis of atopic dermatitis eczema
2. 喘息の遺伝学 genetics of asthma
3. アトピー性皮膚炎（湿疹）の治療 treatment of atopic dermatitis eczema
4. 遺伝性の魚鱗癬の概要 overview of the inherited ichthyoses
5. 成人における刺激性接触皮膚炎 irritant contact dermatitis in adults

English Journal

Murine filaggrin-2 is involved in epithelial barrier function and down-regulated in metabolically induced skin barrier dysfunction.

Hansmann B, Ahrens K, Wu Z, Proksch E, Meyer-Hoffert U, Schröder JM.SourceDepartment of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
Experimental dermatology.Exp Dermatol.2012 Apr;21(4):271-6. doi: 10.1111/j.1600-0625.2012.01449.x.
The S100 fused-type proteins (SFTPs) are thought to be involved in the barrier formation and function of the skin. Mutations in the profilaggrin gene, one of the best investigated members of this family, are known to be the major risk factors for ichthyosis vulgaris and atopic dermatitis. Recently,
PMID 22417302

The Eumelanin Intermediate 5,6-Dihydroxyindole-2-Carboxylic Acid Is a Messenger in the Cross-Talk among Epidermal Cells.

Kovacs D, Flori E, Maresca V, Ottaviani M, Aspite N, Dell'anna ML, Panzella L, Napolitano A, Picardo M, d'Ischia M.SourceLaboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute (IRCCS), Rome, Italy.
The Journal of investigative dermatology.J Invest Dermatol.2012 Apr;132(4):1196-205. doi: 10.1038/jid.2011.457. Epub 2012 Feb 2.
Interest in colorless intermediates of melanocyte metabolism has traditionally been related to their role as melanin precursors, though several lines of evidence scattered in the literature suggested that these compounds may exert an antioxidant and protective function per se unrelated to pigment sy
PMID 22297637

Japanese Journal

フィラグリンの異常とアトピー性皮膚炎 (特集アトピー性皮膚炎の病態解明と治療の進歩)

椛島健治
臨床免疫・アレルギー科 56(3), 284-288, 2011-09
NAID 40019017864

アトピー性皮膚炎におけるフィラグリン遺伝子変異

大口由香,秋山真志,清水宏
日本小児皮膚科学会雑誌 = Journal of pediatric dermatology 29(2), 79-83, 2010-11-30
NAID 10027698373

Related Pictures

★リンクテーブル★

リンク元	「フィラグリン」
拡張検索	「profilaggrin」

「フィラグリン」

Filaggrin
Identifiers
Symbols	FLG; ATOD2
External IDs	OMIM: 135940 HomoloGene: 84700 GeneCards: FLG Gene
Gene Ontology
Molecular function	• structural molecule activity; • calcium ion binding; • nucleoside-triphosphatase activity;
Cellular component	• intermediate filament; • cytoplasmic membrane-bounded vesicle;
Biological process	• multicellular organismal development; • nucleoside triphosphate catabolic process; • keratinocyte differentiation;
	Sources: Amigo / QuickGO
Orthologs
	This box: view; talk; edit;

　　[★]

英: filaggrin
関: プロフィラグリン、ケラチンパターン

顆粒層でプロフィラグリンが脱リン酸化とペプチジルアルギニンデイミナーゼの分解をうけフィラグリンが産生される。ケラチン線維はこのフィラグリンと共に凝集しケラチンパターンと呼ばれる構造を作る。フィラグリンは確執上層で分解され、低分子ペプチドとなり、保湿や紫外線吸収に関与する。

臨床関連

尋常性魚鱗癬：フィラグリン産生低下。
アトピー性皮膚炎：フィラグリン遺伝子の異常が発症に関与。

「profilaggrin」

　　[★]

プロフィラグリン

関: filaggrin

[Ovaere_2009-1] Ovaere P, Lippens S, Vandenabeele P, Declercq W (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.

[pmid16815158-2] 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 (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.

[pmid16550169-3] 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 (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.

[pmid17291859-4] 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 (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 (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.

[pmid18307574-6] Basu K, Palmer CN, Lipworth BJ, Irwin McLean WH, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, Mitra A, Mukhopadhyay S (September 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.

[pmid17531295-7] Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, McLean WH, Mukhopadhyay S (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.

[pmid18325573-8] Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, Mukhopadhyay S, Smith GD, Palmer CN, McLean WH, Irvine AD (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.

[pmid18395550-9] Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN (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.

[pmid18578563-10] Bisgaard H, Simpson A, Palmer CN, Bønnelykke K, McLean I, Mukhopadhyay S, Pipper CB, Halkjaer LB, Lipworth B, Hankinson J, Woodcock A, Custovic A (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.

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filaggrin