Filaggrin
| Identifiers | |
|---|---|
| Symbol | FLG |
| Entrez | 2312 |
| HUGO | 3748 |
| OMIM | 135940 |
| RefSeq | NM_002016 |
| UniProt | P20930 |
| Other data | |
| Locus | Chr. 1 q21.3 |
Filaggrin is a filament-associated protein that binds to keratin fibers in epithelial cells.
Contents |
[edit] 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]
[edit] 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]
[edit] 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]
[edit] See also
[edit] References
- ^ a b Ovaere P, Lippens S, Vandenabeele P, Declercq W. (2009). "The emerging roles of serine protease cascades in the epidermis"Trends in Biochemical Sciences 34 (9): 453–463. doi:10.1016/j.tibs.2009.08.001. PMID 19726197.
- ^ Weidinger S, Illig T, Baurecht H et al (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 et al (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 et al (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. http://www.jci.org/articles/view/1316. Full text at PMC: 508564
- ^ Basu K, Palmer CN, Lipworth BJ, Irwin McLean WH, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, Mitra A, Mukhopadhyay S. (February 2008). "Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults"Allergy E-Pub ahead of print (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): 64–68. doi:10.1016/j.jaci.2007.04.001. PMID 17531295.
- ^ Henderson J, Northstone K, Lee SP, et al. (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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2504043.
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