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词条 Filaggrin
释义

  1. Profilaggrin

  2. Structure

  3. Function

  4. Clinical significance

  5. See also

  6. References

  7. External links

{{Infobox_gene}}Filaggrin (filament aggregating protein) is a filament-associated protein that binds to keratin fibers in epithelial cells. Ten to twelve filaggrin units are post-translationally hydrolyzed from a large profilaggrin precursor protein during terminal differentiation of epidermal cells.[1] In humans, profilaggrin is encoded by the FLG gene, which is part of the S100 fused-type protein (SFTP) family within the epidermal differentiation complex on chromosome 1q21.[2]

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-dependent enzymes.[3]

Structure

Filaggrin is characterized by a particularly high isoelectric point, which is the result of the relatively high presence of histidine in its primary structure.[4] It is also relatively low in the sulfur-containing amino acids methionine and cysteine.

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.[3]

Some studies attribute Filaggrin an important role in keeping the physiological acidic pH of the skin, through a breaking down mechanism to form histidine and subsequently trans-urocanic acid,[5] however others have shown that the filaggrin–histidine–urocanic acid cascade is not essential for skin acidification.[6]

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.[7]

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.[8] 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.[9]

Autoantibodies in rheumatoid arthritis recognizing an epitope of citrullinated peptides are cross-reactive with filaggrin.[10]

The barrier defect seen in filaggrin null carriers also appears to lead to increased asthma susceptibility and exacerbations.[11][12][13] Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression.[14]

In early infancy, the penetrance of filaggrin mutations may be increased by household exposure to cats.[15]

See also

  • Ichthyosis vulgaris
  • List of cutaneous conditions caused by mutations in keratins

References

1. ^{{cite journal | vauthors = Markova NG, Marekov LN, Chipev CC, Gan SQ, Idler WW, Steinert PM | title = Profilaggrin is a major epidermal calcium-binding protein | journal = Molecular and Cellular Biology | volume = 13 | issue = 1 | pages = 613–25 | date = January 1993 | pmid = 8417356 | pmc = 358940 | doi = 10.1128/MCB.13.1.613 | url = http://mcb.asm.org/content/13/1/613.long }}
2. ^{{cite journal | vauthors = Kypriotou M, Huber M, Hohl D | title = The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the 'fused genes' family | journal = Experimental Dermatology | volume = 21 | issue = 9 | pages = 643–9 | date = September 2012 | pmid = 22507538 | doi = 10.1111/j.1600-0625.2012.01472.x }}
3. ^1 {{cite journal | vauthors = Ovaere P, Lippens S, Vandenabeele P, Declercq W | title = The emerging roles of serine protease cascades in the epidermis | journal = Trends in Biochemical Sciences | volume = 34 | issue = 9 | pages = 453–63 | date = September 2009 | pmid = 19726197 | doi = 10.1016/j.tibs.2009.08.001 }}
4. ^{{cite journal | vauthors = Harding CR, Scott IR | title = Histidine-rich proteins (filaggrins): structural and functional heterogeneity during epidermal differentiation | journal = Journal of Molecular Biology | volume = 170 | issue = 3 | pages = 651–73 | date = November 1983 | pmid = 6195345 | doi = 10.1016/s0022-2836(83)80126-0 }}
5. ^{{cite journal | vauthors = Jungersted JM, Scheer H, Mempel M, Baurecht H, Cifuentes L, Høgh JK, Hellgren LI, Jemec GB, Agner T, Weidinger S | title = Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema | journal = Allergy | volume = 65 | issue = 7 | pages = 911–8 | date = July 2010 | pmid = 20132155 | doi = 10.1111/j.1398-9995.2010.02326.x }}
6. ^{{cite journal | vauthors = Fluhr JW, Elias PM, Man MQ, Hupe M, Selden C, Sundberg JP, Tschachler E, Eckhart L, Mauro TM, Feingold KR | title = Is the filaggrin-histidine-urocanic acid pathway essential for stratum corneum acidification? | journal = The Journal of Investigative Dermatology | volume = 130 | issue = 8 | pages = 2141–4 | date = August 2010 | pmid = 20376063 | pmc = 4548931 | doi = 10.1038/jid.2010.74 | url = http://linkinghub.elsevier.com/retrieve/pii/S0022202X15349332 }}
7. ^{{cite journal | vauthors = 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 | title = Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations | journal = The Journal of Allergy and Clinical Immunology | volume = 118 | issue = 1 | pages = 214–9 | date = July 2006 | pmid = 16815158 | doi = 10.1016/j.jaci.2006.05.004 }}
8. ^{{cite journal | vauthors = 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 | title = Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis | journal = The Journal of Allergy and Clinical Immunology | volume = 119 | issue = 2 | pages = 434–40 | date = February 2007 | pmid = 17291859 | doi = 10.1016/j.jaci.2006.12.646 }}
9. ^{{cite journal | vauthors = 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 | title = Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis | journal = Nature Genetics | volume = 38 | issue = 4 | pages = 441–6 | date = April 2006 | pmid = 16550169 | doi = 10.1038/ng1767 }}
10. ^{{cite journal | vauthors = Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ | title = Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies | journal = The Journal of Clinical Investigation | volume = 101 | issue = 1 | pages = 273–81 | date = January 1998 | pmid = 9421490 | pmc = 508564 | doi = 10.1172/JCI1316 | url = http://www.jci.org/articles/view/1316 }}
11. ^{{cite journal | vauthors = Basu K, Palmer CN, Lipworth BJ, McLean WH, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, Mitra A, Mukhopadhyay S | title = Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults | journal = Allergy | volume = 63 | issue = 9 | pages = 1211–7 | date = September 2008 | pmid = 18307574 | doi = 10.1111/j.1398-9995.2008.01660.x | url = http://sro.sussex.ac.uk/2445/1/Allergy.pdf }}
12. ^{{cite journal | vauthors = Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, McLean WH, Mukhopadhyay S | title = Filaggrin null mutations are associated with increased asthma severity in children and young adults | journal = The Journal of Allergy and Clinical Immunology | volume = 120 | issue = 1 | pages = 64–8 | date = July 2007 | pmid = 17531295 | doi = 10.1016/j.jaci.2007.04.001 }}
13. ^{{cite journal | vauthors = Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, Mukhopadhyay S, Smith GD, Palmer CN, McLean WH, Irvine AD | title = The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study | journal = The Journal of Allergy and Clinical Immunology | volume = 121 | issue = 4 | pages = 872–7.e9 | date = April 2008 | pmid = 18325573 | doi = 10.1016/j.jaci.2008.01.026 }}
14. ^{{cite journal | vauthors = Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN | title = A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications | journal = The Journal of Allergy and Clinical Immunology | volume = 121 | issue = 4 | pages = 860–3 | date = April 2008 | pmid = 18395550 | doi = 10.1016/j.jaci.2008.01.015 }}
15. ^{{cite journal | vauthors = Bisgaard H, Simpson A, Palmer CN, Bønnelykke K, McLean I, Mukhopadhyay S, Pipper CB, Halkjaer LB, Lipworth B, Hankinson J, Woodcock A, Custovic A | title = Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure | journal = PLoS Medicine | volume = 5 | issue = 6 | pages = e131 | date = June 2008 | pmid = 18578563 | pmc = 2504043 | doi = 10.1371/journal.pmed.0050131 }}

External links

  • {{MeshName|Filaggrin}}
{{Autoantigens}}{{Cytoskeletal proteins}}

3 : Structural proteins|Genes on human chromosome 1|S100 fused-type proteins
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