The elucidation of the Nagashima-type palmoplantar keratosis caused by SERPINB7 protease inhibitor deficiency

• Project/Area Number: 26461701
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Keio University
• Principal Investigator: SHIOHAMA Aiko 慶應義塾大学, 医学部(信濃町), 特任助教 (40383731)
• Co-Investigator(Kenkyū-buntansha): 佐々木 貴史 慶應義塾大学, 医学部(信濃町), 講師 (70306843) ; 久保 亮治 慶應義塾大学, 医学部(信濃町), 准教授 (70335256)
• Co-Investigator(Renkei-kenkyūsha): MATSUI Takeshi 国立研究開発法人理化学研究所, 統合生命医化学研究センター, 副チームリーダー (10452442)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 皮膚遺伝学 / 遺伝性角化症 / ゲノムシーケンシング / ゲノム解析

Outline of Final Research Achievements

Nagashima-type palmoplantar keratosis (NPPK) was an established autosomal recessive, early-onset palmoplantar keratoderma caused by mutations in the encoding SERPINB7 gene, a member of the serine protease inhibitor superfamily. To gain of more insight of NPPK, we promoted to create a knockout mouse model, selection of protease inhibited the activity of SERPINB7, and genome analysis of NPPK patients.
We identified novel missense mutations of SERPINB7 gene with NPPK. The mutated proteins formed aggregates and mislocalized within corneocytes, possibly resulting in loss of protease inhibitory activity at the proper location. We applied to the haplotype analysis to determine whether the pathogenic mutations were derived from a common ancestor or represented mutations in the genomic region of SERPINB7. In consequence, the founder effect of the mutation and other recurrent mutations might explain why NPPK was so common in the Japanese population but not in Western populations.

Research Products

• [Journal Article] Novel nonsense mutation in SERPINB7 and the treatment of foot odor in a patient with Nagashima-type palmoplantar keratosis. (2017)
  • Author(s): Katsuno M, Shiohama A, Aoki S, Kitamura H, Sasaki T, Amagai M, Kubo A.
  • Journal Title: J Dermatol. Volume: - Issue: 7
  • DOI: 10.1111/1346-8138.13880
  • Peer Reviewed
• [Journal Article] Multiple Primary Acral Lentiginous Melanoma on the Feet Developing in Lesions of Nagashima-type Palmoplantar Keratoderma. (2017)
  • Author(s): Adachi A, Komine M, Maekawa T, Murata S, Shiohama A, Kubo A, Ohtsuki M.
  • Journal Title: Acta Derm Venereol. Volume: - Issue: 6 Pages: 756-758
  • DOI: 10.2340/00015555-2640
  • Peer Reviewed
• [Journal Article] Novel frame-shift mutation in SERPINB7 in a Japanese patient with Nagashima-type palmoplantar keratosis. (2016)
  • Author(s): Nakajima K, Ishiguro M, Shiohama A, Kubo A, Sano S.
  • Journal Title: J Dermatol. Volume: - Issue: 7 Pages: 841-843
  • DOI: 10.1111/1346-8138.13556
  • Peer Reviewed / Open Access
• [Journal Article] Identification and Characterization of a Recessive Missense Mutation p.P277L in SERPINB7 in Nagashima-Type Palmoplantar Keratosis (2016)
  • Author(s): A.Shiohama, T.Sasaki, S.Sato, J.Sakabe, T.Ito, H.Isoda, Y.Zenke, T.Nakano, T.Maeda, A.Ishiko, K.Kabashima, Y.Tokura, Y.Mitsuhashi, M.Amagai, A.Kubo
  • Journal Title: Journal of Investigative Dermatology Volume: 136 Issue: 1 Pages: 325-328
  • DOI: 10.1038/jid.2015.347
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Remarks] 慶應義塾大学病院 医療・健康情報サイトKOMPAS
  • URL: http://kompas.hosp.keio.ac.jp/contents/medical_info/science/201406.html