Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis

Background: Filaggrin is a key protein involved in skin barrier function. Recently, mutations in the filaggrin gene, FLG, were identified in European families with ichthyosis vulgaris (IV) and shown to be an important predisposing factor for atopic dermatitis (AD). Objective: To study the role of FLG mutations in IV/AD in Japan. Methods: The known filaggrin mutations were studied by genotyping and new mutations identified by DNA sequencing. Results: The European-specific mutations R501X and 2282del4 were absent from 253 Japanese individuals. We therefore sequenced the FLG gene in 4 Japanese families with IV and identified 2 novel mutations, 3321delA and S2554X. Immunohistologic and ultrastructural observations indicated that both truncation mutations lead to a striking reduction of keratohyalin granules in the epidermis. We screened 143 Japanese patients with AD for these FLG null mutations and identified them in 8 patients with AD (5.6%), including S2554X in 6 patients (4.2%) and 3321delA in 2 patients (1.4%). Both null variants were absent from 156 unrelated Japanese nonatopic and nonichthyotic controls, giving a significant statistical association between the FLG mutations and AD (chi(2) P value, .0015). This is the first report of FLG mutations in a non-European population. Conclusion: Our data indicate that FLG mutations in Japan are unique from those found in European-origin populations. Clinical implications: Filaggrin null variants are also significant predisposing factors for AD in Japan and, on the basis of the recent European studies, may predict a more severe and persistent form of atopy.