The Majority of Generalized Pustular Psoriasis without Psoriasis Vulgaris Is Caused by Deficiency of Interleukin-36 Receptor Antagonist Kazumitsu Sugiura,

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The Majority of Generalized Pustular Psoriasis without Psoriasis Vulgaris Is Caused by Deficiency of Interleukin-36 Receptor Antagonist Kazumitsu Sugiura, Akemi Takemoto, Michiya Yamaguchi, Hidetoshi Takahashi, Yukiko Shoda, Teruyuki Mitsuma, Kenshiro Tsuda, Emi Nishida, Yaei Togawa, Kimiko Nakajima, Akihiro Sakakibara, Shigeo Kawachi, Makoto Shimizu, Yasutomo Ito, Takuya Takeichi, Michihiro Kono, Yasushi Ogawa, Yoshinao Muro, Akemi Ishida-Yamamoto, Shigetoshi Sano, Hiroyuki Matsue, Akimichi Morita, Hitoshi Mizutani, Hajime Iizuka, Masahiko Muto, Masashi Akiyama Journal of Investigative Dermatology Volume 133, Issue 11, Pages 2514-2521 (November 2013) DOI: 10.1038/jid.2013.230 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Representative clinical features of the two subtypes of generalized pustular psoriasis (GPP): GPP alone and GPP with psoriasis vulgaris (PV). (a, b) GPP alone patient (Patient 2). Pustules on background erythema are seen on the trunk. (c–e) GPP with PV patient (Patient 12). Both pustular lesions (c, d) and psoriatic plaques (e) are observed on the trunk at different times. Journal of Investigative Dermatology 2013 133, 2514-2521DOI: (10.1038/jid.2013.230) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Mutation analysis of IL36RN and analysis of IL36RN messenger RNA (mRNA) from plucked hair samples. (a–c) Representative sequencing data of the patients and controls. (a) Direct sequencing reveals a heterozygous c.28C>T mutation in Patient 2 and homozygous c.28C>T mutations in Patient 5 in exon 2. (b) Direct sequencing reveals a heterozygous c.115+6T>C mutation in Patient 2 in intron 3–4. (c) In Patient 2, who is compound heterozygous for c.28C>T and c.115+6 T>C, normal transcripts and aberrantly spliced, shorter transcripts are identified by reverse transcriptase–PCR (RT–PCR) of IL36RN exon 2–exon 4 mRNA fragments. (d) Direct sequencing of the RT–PCR products shorter than those of normal controls revealed that the aberrant splicing resulted in the skipping of exon 3 in the patient’s IL36RN mRNA. Direct sequencing of RT–PCR products longer than those of normal controls revealed unrelated DNA sequence (data not shown). (e) Second structures of wild-type IL36RN and the mutant IL36RN produced from the mutant alleles. Note the mutant products have no critical residues that mediate the receptor interaction, such as His32, Lys38, Tyr89, Glu94, and Lys96 of IL36RN (Farooq et al., 2013). Journal of Investigative Dermatology 2013 133, 2514-2521DOI: (10.1038/jid.2013.230) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 HLA-A typing and mutation analysis of IL36RN in the family of Patients 24 and 25. HLA-A typing and mutation analysis of IL36RN in the family of Patients 24 and 25. Both patients with generalized pustular psoriasis with psoriasis vulgaris (PV) have the PV-susceptible HLA haplotype HLA-A*0206 as well as the two IL36RN mutations. Journal of Investigative Dermatology 2013 133, 2514-2521DOI: (10.1038/jid.2013.230) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 The linkage disequilibrium (LD) block and the haplotype structure around IL36RN in ethnic Japanese populations. IL36RN structure and the LD block within IL36RN (a) were evaluated using genotype data from the HapMap database. (b) The haplotype structure with eight tag-single-nucleotide polymorphisms (SNPs) was determined using Haploview. Journal of Investigative Dermatology 2013 133, 2514-2521DOI: (10.1038/jid.2013.230) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Representative photos of histopathology of the generalized pustular psoriasis (GPP) skin lesions and distribution of interleukin-36 receptor antagonist (IL36RN). (a–c) (a) Histopathological features of pustular lesions in patients with GPP alone (Patient 4 with IL36RN mutations) and (b) GPP with psoriasis vulgaris (PV) (Patient 12 without any IL36RN mutation) and (c) a typical psoriatic plaque. Characteristic features of psoriasis, acanthosis, hyperkeratosis, and parakeratosis are seen in the epidermis of all the lesions. Pustules are observed in the epidermis of pustular lesions in both (a) the GPP alone patient and (b) the GPP with PV patient. Hematoxylin (HE) and eosin stain; bar=50μm. (d–f) (d) Immunohistochemical staining for IL36RN in the pustular lesions of GPP patients, a GPP alone patient with IL36RN mutations (Patient 4), and (e) GPP with PV patient not carrying any IL36RN mutations (Patient 12), and (f) in a psoriatic plaque as positive control. No IL36RN staining is seen in any part of the epidermis in the GPP alone patient carrying IL36RN mutations, although strong IL36RN labeling is observed in the upper epidermis of the pustular lesion of the GPP with PV patient without any IL36RN mutations and of a typical psoriatic lesion as a positive control. Anti-IL1F5 (IL36RN) antibody stain, bar=50μm. Journal of Investigative Dermatology 2013 133, 2514-2521DOI: (10.1038/jid.2013.230) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions