In 7 unrelated ichthyosis vulgaris (146700) families and 8 additional 'sporadic' cases from Ireland, Scotland, and the U.S., Smith et al. (2006) found that ichthyosis vulgaris was associated with an arg501-to-stop (R501X) mutation arising from a 1501C-to-T transition near the start of repeat 1 in exon 3 of the FLG gene. In 3 families, ichthyosis vulgaris patients with a very pronounced phenotype were homozygous for R501X. In other families and isolated cases, they found individuals with the marked ichthyosis vulgaris phenotype to be compound heterozygous for R501X and a second mutation, 2282del4, in exon 3 (135940.0002). The 2282del4 mutation leads to a premature termination codon 107 bp downstream and, like R501X, stops protein translation within the first filaggrin repeat.
Ichthyosis vulgaris is semidominant: that is, heterozygotes had either no discernible phenotype or milder ichthyosis, whereas homozygotes or compound heterozygotes had marked ichthyosis and an overt histologic skin barrier defect. In an extension of the work of Smith et al. (2006), Palmer et al. (2006) noted that in their families with ichthyosis vulgaris, many individuals null or heterozygous for filaggrin also had atopic dermatitis (605803) (eczema) and, in a few cases, also had asthma (see 600807). Specifically, atopic dermatitis was prevalent in the individuals with mild ichthyosis vulgaris, all of whom were heterozygous for either the R501X or 2282del4 FLG-null allele (13/29; 44%). Atopic dermatitis was particularly common in individuals with severe ichthyosis vulgaris, all of whom were homozygous or compound heterozygous for FLG-null alleles (16/21; 76%). None of the individuals in these families who lacked an FLG-null allele had atopic dermatitis (n = 13). Thus, atopic dermatitis is inherited as a semidominant trait in these families, with high penetrance in FLG-null homozygotes or compound heterozygotes and reduced penetrance in heterozygotes.
Using the transmission-disequilibrium test in 476 German parent-offspring trios with atopic dermatitis, Weidinger et al. (2006) found a significant association between the loss-of-function mutations R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis, allergic sensitization, total IgE level, asthma, and palmar hyperlinearity; there was no significant association with intrinsic atopic dermatitis.
Marenholz et al. (2006) genotyped 1092 children with eczema (atopic dermatitis) from 2 large European populations for the R501X and 2282del4 mutations in the FLG gene and replicated the highly significant association between the null mutations and eczema and concomitant asthma. Moreover, the authors found that these mutations predisposed to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema, and that the mutations predisposed equally to atopic (intrinsic) and nonatopic (extrinsic) forms of eczema. They demonstrated that the presence of 2 null alleles is an independent risk factor for asthma in children with eczema (OR, 11.76, p = 0.0085). Together, the 2 mutations accounted for approximately 11% of eczema cases in the German population.
