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.
| Original language | English |
|---|---|
| Pages (from-to) | 945-956 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 93 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2013 Nov 7 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause nagashima-type palmoplantar keratosis. / Kubo, Akiharu; Shiohama, Aiko; Sasaki, Takashi; Nakabayashi, Kazuhiko; Kawasaki, Hiroshi; Atsugi, Toru; Sato, Showbu; Shimizu, Atsushi; Mikami, Shuji; Tanizaki, Hideaki; Uchiyama, Masaki; Maeda, Tatsuo; Taisuke, Ito; Sakabe, Jun Ichi; Heike, Toshio; Okuyama, Torayuki; Kosaki, Rika; Kosaki, Kenjiro; Kudo, Jun; Hata, Kenichiro; Umezawa, Akihiro; Tokura, Yoshiki; Ishiko, Akira; Niizeki, Hironori; Kabashima, Kenji; Mitsuhashi, Yoshihiko; Amagai, Masayuki.
In: American Journal of Human Genetics, Vol. 93, No. 5, 07.11.2013, p. 945-956.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause nagashima-type palmoplantar keratosis
AU - Kubo, Akiharu
AU - Shiohama, Aiko
AU - Sasaki, Takashi
AU - Nakabayashi, Kazuhiko
AU - Kawasaki, Hiroshi
AU - Atsugi, Toru
AU - Sato, Showbu
AU - Shimizu, Atsushi
AU - Mikami, Shuji
AU - Tanizaki, Hideaki
AU - Uchiyama, Masaki
AU - Maeda, Tatsuo
AU - Taisuke, Ito
AU - Sakabe, Jun Ichi
AU - Heike, Toshio
AU - Okuyama, Torayuki
AU - Kosaki, Rika
AU - Kosaki, Kenjiro
AU - Kudo, Jun
AU - Hata, Kenichiro
AU - Umezawa, Akihiro
AU - Tokura, Yoshiki
AU - Ishiko, Akira
AU - Niizeki, Hironori
AU - Kabashima, Kenji
AU - Mitsuhashi, Yoshihiko
AU - Amagai, Masayuki
PY - 2013/11/7
Y1 - 2013/11/7
N2 - "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.
AB - "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.
UR - http://www.scopus.com/inward/record.url?scp=84890213862&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890213862&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2013.09.015
DO - 10.1016/j.ajhg.2013.09.015
M3 - Article
C2 - 24207119
AN - SCOPUS:84890213862
VL - 93
SP - 945
EP - 956
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -