Filaggrin Mutations in Children with Severe Atopic Dermatitis

Abstract

Atopic dermatitis (AD) results from strong genetic and environmental interactions. AD shows genetic linkage to Chromosome 1q21. This region contains the epidermal differentiation complex (EDC), which consists of genes that form essential components of epidermal surfaces. Filaggrin (FLG) is one of these. Mutations in FLG/(R501X and 2282del4) are reported to be strongly associated with AD and to influence asthma accompanying AD. We investigated these effects in families recruited through a child with severe AD. We genotyped two panels of families, totalling 426, containing 990 affected and unaffected children. We found significant associations with AD (P=0.0001), asthma (P=0.006), and atopy (P=0.002). The FLG mutations were present in 26.7% of patients with AD, but were also present in 14.4% of children without AD. They were weakly associated with disease severity. The variants were not independently associated with asthma. The overall LOD score for genetic linkage of markers to the region was 3.57. This fell to 2.03 after accounting for the FLG mutations, indicating the presence of other genetic variants influencing AD at this locus. Our results provide further confirmation of the importance of mutations in FLG and the skin barrier in AD pathogenesis. The results indicate that investigations of other genes within the EDC should be undertaken.

Filaggrin null mutations are associated with atopic dermatitis and elevated levels of IgE in the Japanese population: a family and case–control study

“…A number of studies have been conducted to replicate the original findings, and some have confirmed and others refuted the association of FLG with AD (Marenholz et al 2006;Ruether et al 2006;Weidinger et al 2006Weidinger et al , 2007Barker et al 2007;Morar et al 2007;Stemmler et al 2007). To examine the association of common FLG variants with AD development, we performed tSNP analysis of Japanese AD families and case-control subjects.…”

New insights in the pathogenesis of atopic dermatitis

“…However, the majority of AD patients do not carry FLG. In children, FLG accounts for only 26.7% of the patients with AD, suggesting that other skin barrier genes, particularly those in the epidermal differentiation complex of chromosome 1q21, likely exist to account for the barrier defects in AD patients without FLG (10,11). Abnormalities in skin lipid composition (6), excessive serine protease activity (as illustrated by the ichthyosiform disease Netherton syndrome, which is caused by mutations in SPINK5 that encodes for lymphoepithelial Kazal-type-related inhibitor) (6), claudins of tight junction (12), or suppression of skin barrier protein expression by inflammation (9) may constitute other causes of skin barrier defects in AD.…”

Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults

“…These genetic mutations, previously proven to impair the formation of stratum corneum (5), strongly predispose to childhood eczema in several white European populations, where these mutations are prevalent (3,(6)(7)(8)(9)(10)(11), including Scottish, English, Irish, Danish and German populations. Analogous mutations leading to loss of function have Background: Filaggrin (FLG) null mutations are important genetic predisposing factors for atopic asthma and have recently been shown to influence controller and reliever medication needs in asthmatic children.…”