2. Academic Validation
  3. Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis

Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis

  • Am J Hum Genet. 2013 Nov 7;93(5):945-56. doi: 10.1016/j.ajhg.2013.09.015.
Akiharu Kubo 1,  Aiko Shiohama,  Takashi Sasaki,  Kazuhiko Nakabayashi,  Hiroshi Kawasaki,  Toru Atsugi,  Showbu Sato,  Atsushi Shimizu,  Shuji Mikami,  Hideaki Tanizaki,  Masaki Uchiyama,  Tatsuo Maeda,  Taisuke Ito,  Jun-ichi Sakabe,  Toshio Heike,  Torayuki Okuyama,  Rika Kosaki,  Kenjiro Kosaki,  Jun Kudoh,  Kenichiro Hata,  Akihiro Umezawa,  Yoshiki Tokura,  Akira Ishiko,  Hironori Niizeki,  Kenji Kabashima,  Yoshihiko Mitsuhashi,  Masayuki Amagai
Affiliations

Affiliation

  • 1 Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo 160-8582, Japan; Center for Integrated Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: akiharu@a5.keio.jp.
PMID: 24207119 DOI: 10.1016/j.ajhg.2013.09.015
Abstract

"Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger Sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the Serine Protease Inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.

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