Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis Toshifumi Nomura, MD, Aileen Sandilands, PhD,

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Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis Toshifumi Nomura, MD, Aileen Sandilands, PhD, Masashi Akiyama, MD, PhD, Haihui Liao, MD, Alan T. Evans, MD, Kaori Sakai, Mitsuhito Ota, MD, PhD, Hisashi Sugiura, MD, PhD, Kazuo Yamamoto, MD, PhD, Hiroshi Sato, MD, PhD, Colin N.A. Palmer, PhD, Frances J.D. Smith, PhD, W.H. Irwin McLean, PhD, DSc, FRSE, Hiroshi Shimizu, PhD Journal of Allergy and Clinical Immunology Volume 119, Issue 2, Pages 434-440 (February 2007) DOI: 10.1016/j.jaci.2006.12.646 Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Clinical features of patients with IV. A, Marked, adherent scales were clearly visible on the pretibial region of a 3321delA heterozygote from family 3. B, Fine, white, and branny scales on the pretibial region of the proband, S2554X heterozygote, in family 1. C, Marked plantar hyperlinearity seen in the S2554X homozygote from family 1. D, In contrast, the S2554X heterozygote in family 1 presented with a less marked plantar hyperlinearity. This clearly shows that IV is inherited as a semidominant trait. E, Marked lichenification on the left antecubital fossa of a patient with AD who was heterozygous for 3321delA. F, Itchy excoriated papules on the trunk of a patient with AD who was heterozygous for S2554X. Journal of Allergy and Clinical Immunology 2007 119, 434-440DOI: (10.1016/j.jaci.2006.12.646) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Detection of FLG mutation, S2554X. A, A pedigree of ichthyosis vulgaris family 1, showing the semidominant inheritance pattern. Solid symbols refer to the marked ichthyosis vulgaris presentation; cross-hatched symbols refer to the milder ichthyosis vulgaris presentation. In addition, 4 individuals also had atopic dermatitis. ∗Individuals with a dermatologist-diagnosed atopic dermatitis. homo, Homozygous for S2554X; hetero, heterozygous for S2554X; wt, wild type for S2554X. B, Normal control sequence from filaggrin repeat 7 in exon 3 identified in III-2 as shown in A, corresponding to codons 2552-2556. A heterozygous transition mutation c.7661C→G was identified in II-2 (the proband), resulting in S2554X. A homozygous transition mutation c.7661C→G in filaggrin repeat 7 in exon 3 was identified in II-1, resulting in nonsense mutation, S2554X. C, Screening for the mutation S2554X by Hpy188 I restriction digest. The mutant alleles were resolved into 231-bp, 204-bp, and 77-bp bands, whereas the wild-type alleles were resolved into 231-bp, 159-bp, 77-bp, and 45-bp bands. In this analysis, 45-bp and 77-bp alleles were resolved into a single band on a 3% agarose gel. The PCR product from the proband (heterozygote) in family 1 was resolved into 5 bands. Journal of Allergy and Clinical Immunology 2007 119, 434-440DOI: (10.1016/j.jaci.2006.12.646) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Detection of FLG mutation, 3321delA. A, A heterozygous deletion mutation in filaggrin repeat 2 in exon 3, 3321delA, was identified in the proband from family 3. Normal control sequence from filaggrin repeat 2 in exon 3, corresponding to codons 1105-1110. hetero, Heterozygous for 3321delA; wt, wild type for 3321delA. B, Screening for the mutation 3321delA by sizing a fluorescent labeled PCR fragment. The wild-type allele was identified as a 160-bp peak, and the 3321delA allele as a 159-bp peak. Journal of Allergy and Clinical Immunology 2007 119, 434-440DOI: (10.1016/j.jaci.2006.12.646) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Histologic features of the patients with IV. A-C, Hematoxylin and eosin staining. Both the 3321delA heterozygote in family 3 (A) and the S2554X homozygote in family 1 (B) showed a lack of granular layers in the epidermis, where only a small amount of basophilic substance (arrows), resembling keratohyalin, was occasionally present. In contrast, normal control skin (C) had abundant keratohyalin granules in the granular layers. D-F, Immunohistochemical staining using antifilaggrin mAbs against an epitope conserved in all filaggrin repeat peptides. Both the 3321delA heterozygote in family 3 (D) and the S2554X homozygote in family 1 (E) showed a marked reduction in staining for filaggrin, whereas normal control skin (F) stained strongly. G-I, Electron microscopic observation of the granular layers. Both the 3321delA heterozygote in family 3 (G) and the S2554X homozygote in family 1 (H) exhibited an apparent loss of keratohyalin granules, although small keratin filament aggregates (arrows) were observed in granular layer keratinocytes, perhaps corresponding to the residual keratohyalin seen histologically. In normal control skin (I), a normal amount of keratohyalin granules (∗) was confirmed. Journal of Allergy and Clinical Immunology 2007 119, 434-440DOI: (10.1016/j.jaci.2006.12.646) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions