2 NULL ALLELES IN FILAGGRIN CAUSE ICHTHYOSIS VULGARIS AND PREDISPOSE TO ATOPIC

Ichthyosis vulgaris (IV; OMIM # 146700) is the most common inherited disorders of keratinization and one of the most frequent single gene disorders in humans. Atopic disease, including atopic dermatitis, allergy and asthma, has increased dramatically in the developed world, with prevalence increased two-to threefold over the past 30 years. Twin and family studies have demonstrated a strong genetic predisoposition. Although most studies have focused on immunological mechanisms, a primary epithelial barrier defect in atopic dermatitis (AD) has been anticipated. Previous genome wide screens have suggesting linkage to a number of possible loci, including the human epidermal differentiation complex (EDC) on chromosome 1q21. Filaggrin is a key protein encoded for in the EDC that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Initially we studied five extended Irish familes with IV. In our families we examined linkage between ichthyosis vulgaris phenotype and the filagrin null-alleles R510X and 2282del4. The maximum combined 2-point lod score for our families was 8.11 at θ=0, indicating strong linkage to these variants. Many individuals in these families also had AD. When we rescored these families for AD we were still able to achieve a significant two-point lod score, Zmax = 3.27 with no recombination observed (θ = 0), where penetrance in heterozygotes and homozygotes was set at 45%