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]
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]
↑ 3.03.1Ovaere P, Lippens S, Vandenabeele P, Declercq W (September 2009). "The emerging roles of serine protease cascades in the epidermis". Trends in Biochemical Sciences. 34 (9): 453–63. doi:10.1016/j.tibs.2009.08.001. PMID19726197.
↑Harding CR, Scott IR (November 1983). "Histidine-rich proteins (filaggrins): structural and functional heterogeneity during epidermal differentiation". Journal of Molecular Biology. 170 (3): 651–73. doi:10.1016/s0022-2836(83)80126-0. PMID6195345.
↑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". The Journal of Allergy and Clinical Immunology. 118 (1): 214–9. doi:10.1016/j.jaci.2006.05.004. PMID16815158.
↑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". The Journal of Allergy and Clinical Immunology. 119 (2): 434–40. doi:10.1016/j.jaci.2006.12.646. PMID17291859.
↑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". Nature Genetics. 38 (4): 441–6. doi:10.1038/ng1767. PMID16550169.
↑Basu K, Palmer CN, Lipworth BJ, 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. PMID18307574.
↑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". The Journal of Allergy and Clinical Immunology. 120 (1): 64–8. doi:10.1016/j.jaci.2007.04.001. PMID17531295.
↑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". The Journal of Allergy and Clinical Immunology. 121 (4): 872–7.e9. doi:10.1016/j.jaci.2008.01.026. PMID18325573.
↑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". The Journal of Allergy and Clinical Immunology. 121 (4): 860–3. doi:10.1016/j.jaci.2008.01.015. PMID18395550.