Communicated by Ravi Savarirayan
Mutation Analysis of the IL36RN Gene in 14 Japanese Patients with Generalized Pustular Psoriasis
Article first published online: 11 OCT 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 1, pages 176–183, January 2013
How to Cite
Farooq, M., Nakai, H., Fujimoto, A., Fujikawa, H., Matsuyama, A., Kariya, N., Aizawa, A., Fujiwara, H., Ito, M. and Shimomura, Y. (2013), Mutation Analysis of the IL36RN Gene in 14 Japanese Patients with Generalized Pustular Psoriasis. Hum. Mutat., 34: 176–183. doi: 10.1002/humu.22203
Contract grant sponsors: The Special Coordination Funds for Promoting Science and Technology, the Ministry of Education, Culture, Sports, Science and Technology, Japan (to Y.S.); “Research on Measures for Intractable Diseases” Project: matching fund subsidy (H23–028) from Ministry of Health, Labour, and Welfare, Japan.
- Issue published online: 20 DEC 2012
- Article first published online: 11 OCT 2012
- Accepted manuscript online: 17 AUG 2012 04:12PM EST
- Manuscript Accepted: 31 JUL 2012
- Manuscript Received: 6 MAY 2012
- Special Coordination Funds for Promoting Science and Technology
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Ministry of Health, Labour, and Welfare, Japan
- generalized pustular psoriasis;
- exon skipping
Generalized pustular psoriasis (GPP) is a rare, potentially life threatening, and aggressive form of psoriasis, which is characterized by sudden onset with repeated episodic skin inflammation leading to pustule formation. Familial GPP is known to be caused by recessively inherited mutations in the IL36RN gene, which encodes interleukin 36 receptor antagonist (IL-36Ra). In this article, we performed mutation analysis of the IL36RN gene in 14 Japanese patients with GPP, and identified mutations in two of these patients analyzed. One patient was compound heterozygous for mutations c.115+6T>C and c.368C>G (p.Thr123Arg), whereas the other carried compound heterozygous mutations c.28C>T (p.Arg10*) and c.115+6T>C in the IL36RN gene. Expression studies using total RNA from the patients’ skin revealed that the mutation c.115+6T>C resulted in skipping of exon 3, leading to a frameshift and a premature termination codon (p.Arg10Argfs*1). The protein structure analysis suggested that the missense mutation p.Thr123Arg caused misfolding and instability of IL-36Ra protein. In vitro studies in cultured cells showed impaired expression of the p.Thr123Arg mutant IL-36Ra protein, which failed to antagonize the IL-36 signaling pathway. Our data further underscore the critical role of IL36RN in pathogenesis of GPP.