Filaggrin Gene Mutations with Special Reference to Atopic Dermatitis
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Urticaria and Atopic Dermatitis (M Furue and T Nakahara, Section Editors)
Filaggrin Gene Mutations with Special Reference to Atopic Dermatitis Jayanta Gupta, M.D., Ph.D1 David J. Margolis, M.D., Ph.D2,* Address 1 Department of Health Sciences, Marieb College of Health & Human Services, Florida Gulf Coast University, Fort Myers, FL, USA *,2 Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA Email: [email protected]
* Springer Nature Switzerland AG 2020
This article is part of the Topical Collection on Urticaria and Atopic Dermatitis Keywords Filaggrin gene I Mutation I Polymorphism I Atopic dermatitis I Eczema
Abstract Purpose of review Mutations in the filaggrin gene can cause absent or reduced filaggrin protein, leading to impaired keratinization and skin barrier defect, which produce characteristic phenotypes. In this short review, we report current evidence on the topic with special reference to atopic dermatitis, suggest future directions, and discuss therapeutic implications. Recent findings Numerous candidate gene association studies, genome-wide association studies, studies on copy number variations, and, most recently, sequencing studies have confirmed the robust association of mutations in the filaggrin gene with atopic dermatitis, and have also linked these mutations with several other disorders. Summary Filaggrin gene defects remain the strongest identified genetic risk factors for atopic dermatitis. Taken in conjunction with other genes found to be associated with this condition, genetic screening and identification of individuals at risk for atopic dermatitis could lead to personalized therapy. Manipulation of genetic regulatory elements to increase the amount of filaggrin protein in deficient individuals is an attractive treatment option for the future.
Introduction The filaggrin gene (FLG) is one of the 70 genes forming the Epidermal differentiation complex (EDC), a 2 MB region
located on human chromosome 1q21. These genes are responsible for the maturation of keratinocytes, which
Urticaria and Atopic Dermatitis (M Furue and T Nakahara, Section Editors) are the chief cells in human epidermis. Keratinocytes play a crucial role in maintaining an intact skin barrier. In 2006, two landmark studies from Dr. WH McLean’s group demonstrated the association of loss-of-function (LOF) mutations in FLG with ichthyosis vulgaris [1••], a condition characterized by impaired keratinization resulting from either homozygous or compound heterozygous mutations in the gene that has a dominant/semi-dominant mode of inheritance, and atopic dermatitis (AD) [2••], a complex disorder characterized by an impaired skin barrier in the presence of an allergic milieu. Since then, numerous
studies have replicated the FLG-AD association from the original study, and several other variants in FLG have been shown to be associated with AD. Indeed, the strength of association between FLG and AD is exceptionally high for a comple
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