DO: 0110098;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q21.3 | {Dermatitis, atopic, susceptibility to, 2} | 605803 | 3 | FLG | 135940 |
A number sign (#) is used with this entry because of evidence that susceptibility to atopic dermatitis (ATOD2) linked to chromosome 1q21 is conferred by variation in the FLG gene (135940).
For a clinical description of atopic dermatitis and an overview of linkage studies, see 603165.
Cookson et al. (2001) identified linkage of atopic dermatitis to chromosome 1q21 at markers D1S252 and D1S498. The marker D1S498 is linked to psoriasis (PSORS4; 603935).
In genotype and haplotype analysis of 2 independent cohorts of 128 psoriasis triads and 120 atopic dermatitis triads, Giardina et al. (2006) detected a significant association between haplotypes defined by MIDDLE and ENDAL16 markers and psoriasis (p = 0.0000036) and atopic dermatitis (p = 0.0276), colocalizing within a 42-kb interval on chromosome 1q21 containing a single gene, LOR (152445). Analysis of LOR SNPs from regulatory and coding regions did not show evidence of association for either of the 2 diseases, but expression profiles of LOR in skin biopsies showed reduced levels in psoriasis and increased levels in atopic dermatitis, suggesting a specific misregulation of LOR mRNA production.
The FLG gene encodes a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Palmer et al. (2006) showed that 2 independent loss-of-function genetic variants in the FLG gene, R501X (135940.0001) and 2282del4 (135940.0002), are very strong predisposing factors for atopic dermatitis. These mutations had been shown to be the cause of ichthyosis vulgaris (146700) in 15 families and isolated cases by Smith et al. (2006). The R501X and 2282del4 variants, carried by approximately 9% of people of European origin, also showed highly significant association with asthma (see 600807) occurring in the context of atopic dermatitis.
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 1,092 children with eczema (atopic dermatitis) from 2 large European populations for the R501X and 2282del4 mutations in the FLG gene and confirmed a 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 was an independent risk factor for asthma in children with eczema (OR, 11.76, p = 0.0085). Together, the 2 mutations accounted for an estimated 11% of eczema cases in the German population. Noting that previous expression of eczema was a prerequisite for the manifestation of allergic airways disease and specific sensitization, Marenholz et al. (2006) emphasized the importance of the epidermal barrier in the pathogenesis of these disorders (the so-called 'atopic march').
Nomura et al. (2007) studied 143 Japanese patients with atopic dermatitis from 140 unrelated families who were negative for known mutations in the FLG gene, screening them for 2 novel FLG mutations that the authors had identified in Japanese ichthyosis vulgaris patients, S2554X (135940.0003) and 3321delA (135940.0004). The S2554X mutation was identified in 6 patients and 3321delA in 2 patients; neither was found in 156 unrelated Japanese nonatopic and nonichthyotic controls, yielding a chi-square p value of 0.0015. Noting that the R501X and 2282del4 mutations were absent from a total of 253 Japanese individuals, including their patients with ichthyosis vulgaris and atopic dermatitis, Nomura et al. (2007) concluded that FLG mutations in Japan are different from those found in European-origin populations.
Cookson, W. O. C. M., Ubhi, B., Lawrence, R., Abecasis, G. R., Walley, A. J., Cox, H. E., Coleman, R., Leaves, N. I., Trembath, R. C., Moffatt, M. F., Harper, J. I. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nature Genet. 27: 372-373, 2001. [PubMed: 11279517] [Full Text: https://doi.org/10.1038/86867]
Giardina, E., Sinibaldi, C., Chini, L., Moschese, V., Marulli, G., Provini, A., Rossi, P., Paradisi, M., Chimenti, S., Galli, E., Brunetti, E., Girolomoni, G., Novelli, G. Co-localization of susceptibility loci for psoriasis (PSORS4) and atopic dermatitis (ATOD2) on human chromosome 1q21. Hum. Hered. 61: 229-236, 2006. [PubMed: 16912508] [Full Text: https://doi.org/10.1159/000095059]
Marenholz, I., Nickel, R., Ruschendorf, F., Schulz, F., Esparza-Gordillo, J., Kerscher, T., Gruber, C., Lau, S., Worm, M., Keil, T., Kurek, M., Zaluga, E., Wahn, U., Lee, Y.-A. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J. Allergy Clin. Immun. 118: 866-871, 2006. [PubMed: 17030239] [Full Text: https://doi.org/10.1016/j.jaci.2006.07.026]
Nomura, T., Sandilands, A., Akiyama, M., Liao, H., Evans, A. T., Sakai, K., Ota, M., Sugiura, H., Yamamoto, K., Sato, H., Palmer, C. N. A., Smith, F. J. D., McLean, W. H. I., Shimizu, H. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J. Allergy Clin. Immun. 119: 434-440, 2007. [PubMed: 17291859] [Full Text: https://doi.org/10.1016/j.jaci.2006.12.646]
Palmer, C. N. A., Irvine, A. D., Terron-Kwiatkowski, A., Zhao, Y., Liao, H., Lee, S. P., Goudie, D. R., Sandilands, A., Campbell, L. E., Smith, F. J. D., O'Regan, G. M., Watson, R. M., and 15 others. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genet. 38: 441-446, 2006. [PubMed: 16550169] [Full Text: https://doi.org/10.1038/ng1767]
Smith, F. J. D., Irvine, A. D., Terron-Kwiatkowski, A., Sandilands, A., Campbell, L. E., Zhao, Y., Liao, H., Evans, A. T., Goudie, D. R., Lewis-Jones, S., Arseculeratne, G., Munro, C. S., Sergeant, A., O'Regan, G., Bale, S. J., Compton, J. G., DiGiovanna, J. J., Presland, R. B., Fleckman, P., McLean, W. H. I. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature Genet. 38: 337-342, 2006. [PubMed: 16444271] [Full Text: https://doi.org/10.1038/ng1743]
Weidinger, S., Illig, T., Baurecht, H., Irvine, A. D., Rodriquez, E., Diaz-Lacava, A., Klopp, N., Wagenpfeil, S., Zhao, Y., Liao, H., Lee, S. P., Palmer, C. N. A., Jenneck, C., Maintz, L., Hagemann, T., Behrendt, H., Ring, J., Nothen, M. M., McLean, W. H. I., Novak, N. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J. Allergy Clin. Immun. 118: 214-219, 2006. Note: Erratum: J. Allergy Clin. Immun. 118: 922 only, 2006. Erratum: J. Allergy Clin. Immun. 118: 724 only, 2006. [PubMed: 16815158] [Full Text: https://doi.org/10.1016/j.jaci.2006.05.004]