title: Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.
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.
authors.affiliation: 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.
authors.forename: Akiharu
authors.initials: A
authors.lastname: Kubo
authors.forename: Aiko
authors.initials: A
authors.lastname: Shiohama
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Toru
authors.initials: T
authors.lastname: Atsugi
authors.forename: Showbu
authors.initials: S
authors.lastname: Sato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimizu
authors.forename: Shuji
authors.initials: S
authors.lastname: Mikami
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tanizaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Maeda
authors.forename: Taisuke
authors.initials: T
authors.lastname: Ito
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sakabe
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.forename: Torayuki
authors.initials: T
authors.lastname: Okuyama
authors.forename: Rika
authors.initials: R
authors.lastname: Kosaki
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
authors.forename: Jun
authors.initials: J
authors.lastname: Kudoh
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tokura
authors.forename: Akira
authors.initials: A
authors.lastname: Ishiko
authors.forename: Hironori
authors.initials: H
authors.lastname: Niizeki
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Mitsuhashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D015843:Serpins / Q000235:genetics*; D055815:Young Adult
chemical_list: C114170:SERPINB7 protein, human; D015843:Serpins