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FLG gene

filaggrin
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Normal Function

The FLG gene provides instructions for making a large protein called profilaggrin, which is found in cells that make up the outermost layer of skin (the epidermis). Profilaggrin is cut (cleaved) to produce multiple copies of the filaggrin protein, which is important for the structure of the epidermis. The profilaggrin molecule can contain 10, 11, or 12 copies of the filaggrin protein, depending on the genetics of the individual. Further processing of the filaggrin protein produces other molecules that play a role in hydration of the skin.

The epidermis acts as a barrier to help minimize water loss and protect the body from foreign substances, including toxins, bacteria, and substances that can cause allergic reactions (allergens), such as pollen and dust mites. Filaggrin plays an important role in the skin's barrier function. It brings together structural proteins in the outermost skin cells to form tight bundles, flattening and strengthening the cells to create a strong barrier. In addition, processing of filaggrin proteins leads to production of molecules that are part of the skin's "natural moisturizing factor," which helps maintain hydration of the skin. These molecules also maintain the correct acidity (pH) of the skin, which is another important aspect of the barrier.

Health Conditions Related to Genetic Changes

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Atopic dermatitis

Mutations in the FLG gene are strongly associated with a skin disorder called atopic dermatitis (also known as atopic eczema). This condition is characterized by dry, itchy skin and red rashes. Twenty to 30 percent of people with atopic dermatitis have an FLG gene mutation compared with 8 to 10 percent of the general population without atopic dermatitis. Having a mutation in this gene only increases the risk of developing atopic dermatitis. Not everyone with an FLG gene mutation will develop the disorder. Other genes and environmental factors contribute to atopic dermatitis. Individuals with a mutation in both copies of the FLG gene are at greater risk of developing atopic dermatitis than those with a mutation in only one copy of the gene. The condition is typically more severe in people with two mutated copies.

In addition to FLG gene mutations, the number of filaggrin proteins produced from each profilaggrin molecule is associated with development of atopic dermatitis; individuals with genetic instructions for producing 10 copies are at greater risk of developing the disorder than those with instructions for producing 11 or 12 copies.

Approximately 40 mutations in the FLG gene have been identified in people with atopic dermatitis. These mutations lead to production of an abnormally short profilaggrin molecule that cannot be cleaved to produce filaggrin proteins. The resulting shortage of filaggrin can impair the barrier function of the skin. Further, a lack of filaggrin leads to a shortage of natural moisturizing factor, which allows excess water to be lost through the skin and causes dry skin in affected individuals.

Research suggests that the impairment of the skin's barrier function caused by a shortage of filaggrin contributes to development of allergic disorders. Atopic dermatitis is not initially caused by an allergic reaction, although sometimes substances that can cause allergic reactions (allergens) are thought to contribute to flare-ups of the rashes. In addition, people with atopic dermatitis have an increased likelihood of developing other allergic disorders, including asthma, hay fever, and food allergies. (The tendency to develop allergic disorders is known as atopy.)

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Other disorders

More than 40 FLG gene mutations have been found to cause a relatively common skin disorder called ichthyosis vulgaris, which is characterized by dry, scaly skin, particularly during the winter when humidity in the air is low. Affected individuals can also have unusually prominent creases on the palms of their hands and soles of their feet (palmar and plantar hyperlinearity) and an increased risk of allergic disorders, including atopic dermatitis (described above). Typically, individuals with a mutation in one copy of the FLG gene are mildly affected; they may have symptoms only seasonally, or they may never have obvious skin problems. Individuals with two mutated copies of the gene have more severe symptoms that may be present year-round.

Some of the mutations associated with atopic dermatitis are also found in people with ichthyosis vulgaris. As in atopic dermatitis, the mutations lead to production of an abnormally short profilaggrin molecule that cannot be cleaved to produce filaggrin proteins. A lack of filaggrin and the molecules produced from its processing lead to the dry, scaly skin characteristic of ichthyosis vulgaris. Impairment of the skin's barrier function likely contributes to the development of allergic diseases in some people with ichthyosis vulgaris. Individuals with FLG gene mutations have an increased risk of developing asthma, but only if they also have atopic dermatitis. FLG gene mutations also increase the risk of hay fever, food allergies, and skin sensitivity to nickel, regardless of whether the person has atopic dermatitis. Additional factors, such as living with a cat and smoking tobacco products, may increase the risk of atopic dermatitis and asthma, respectively, in people with ichthyosis vulgaris.

Other Names for This Gene

  • ATOD2
  • epidermal filaggrin

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Brown SJ, McLean WH. One remarkable molecule: filaggrin. J Invest Dermatol. 2012 Mar;132(3 Pt 2):751-62. doi: 10.1038/jid.2011.393. Epub 2011 Dec 8. Review. Citation on PubMed or Free article on PubMed Central
  • Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011 Oct 6;365(14):1315-27. doi: 10.1056/NEJMra1011040. Review. Citation on PubMed
  • Liang Y, Chang C, Lu Q. The Genetics and Epigenetics of Atopic Dermatitis-Filaggrin and Other Polymorphisms. Clin Rev Allergy Immunol. 2016 Dec;51(3):315-328. Review. Citation on PubMed
  • 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. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006 Apr;38(4):441-6. Epub 2006 Mar 19. Citation on PubMed
  • Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ, Irvine AD, Weidinger S. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol. 2009 Jun;123(6):1361-70.e7. doi: 10.1016/j.jaci.2009.03.036. Citation on PubMed
  • Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O'Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006 Mar;38(3):337-42. Epub 2006 Jan 29. Citation on PubMed
  • Thyssen JP, Godoy-Gijon E, Elias PM. Ichthyosis vulgaris: the filaggrin mutation disease. Br J Dermatol. 2013 Jun;168(6):1155-66. doi: 10.1111/bjd.12219. Epub 2013 May 6. Review. Citation on PubMed
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