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Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads

Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate kera... Full description

Journal Title: American journal of human genetics 2015-03-05, Vol.96 (3), p.440-447
Main Author: Lin, Zhimiao
Other Authors: Zhao, Jiahui , Nitoiu, Daniela , Scott, Claire A , Plagnol, Vincent , Smith, Frances J.D , Wilson, Neil J , Cole, Christian , Schwartz, Mary E , McLean, W.H. Irwin , Wang, Huijun , Feng, Cheng , Duo, Lina , Zhou, Eray Yihui , Ren, Yali , Dai, Lanlan , Chen, Yulan , Zhang, Jianguo , Xu, Xun , O’Toole, Edel A , Kelsell, David P , Yang, Yong
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
Link: https://www.ncbi.nlm.nih.gov/pubmed/25683118
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4375526
title: Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads
format: Article
creator:
  • Lin, Zhimiao
  • Zhao, Jiahui
  • Nitoiu, Daniela
  • Scott, Claire A
  • Plagnol, Vincent
  • Smith, Frances J.D
  • Wilson, Neil J
  • Cole, Christian
  • Schwartz, Mary E
  • McLean, W.H. Irwin
  • Wang, Huijun
  • Feng, Cheng
  • Duo, Lina
  • Zhou, Eray Yihui
  • Ren, Yali
  • Dai, Lanlan
  • Chen, Yulan
  • Zhang, Jianguo
  • Xu, Xun
  • O’Toole, Edel A
  • Kelsell, David P
  • Yang, Yong
subjects:
  • Adult
  • Apoptosis - genetics
  • Calcium-Binding Proteins - genetics
  • Calcium-Binding Proteins - metabolism
  • Causes of
  • Cell Adhesion - genetics
  • Cheilitis - genetics
  • Chromatin
  • Epidermis - metabolism
  • Female
  • Gene mutations
  • Genetic disorders
  • Genetic research
  • Genetics
  • Genetics(clinical)
  • Homozygote
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Keratinocytes
  • Keratosis - genetics
  • Male
  • Middle Aged
  • Mutation
  • Nail Diseases - genetics
  • Pedigree
  • Proteases
  • Proteins
  • Report
  • Research
  • RNA, Small Interfering - genetics
  • RNA, Small Interfering - metabolism
  • Skin - pathology
  • Skin Diseases - genetics
ispartof: American journal of human genetics, 2015-03-05, Vol.96 (3), p.440-447
description: Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleLoss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads
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creatorLin, Zhimiao ; Zhao, Jiahui ; Nitoiu, Daniela ; Scott, Claire A ; Plagnol, Vincent ; Smith, Frances J.D ; Wilson, Neil J ; Cole, Christian ; Schwartz, Mary E ; McLean, W.H. Irwin ; Wang, Huijun ; Feng, Cheng ; Duo, Lina ; Zhou, Eray Yihui ; Ren, Yali ; Dai, Lanlan ; Chen, Yulan ; Zhang, Jianguo ; Xu, Xun ; O’Toole, Edel A ; Kelsell, David P ; Yang, Yong
creatorcontribLin, Zhimiao ; Zhao, Jiahui ; Nitoiu, Daniela ; Scott, Claire A ; Plagnol, Vincent ; Smith, Frances J.D ; Wilson, Neil J ; Cole, Christian ; Schwartz, Mary E ; McLean, W.H. Irwin ; Wang, Huijun ; Feng, Cheng ; Duo, Lina ; Zhou, Eray Yihui ; Ren, Yali ; Dai, Lanlan ; Chen, Yulan ; Zhang, Jianguo ; Xu, Xun ; O’Toole, Edel A ; Kelsell, David P ; Yang, Yong
descriptionCalpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.
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languageeng
publisherUnited States: Elsevier Inc
subjectAdult ; Apoptosis - genetics ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Causes of ; Cell Adhesion - genetics ; Cheilitis - genetics ; Chromatin ; Epidermis - metabolism ; Female ; Gene mutations ; Genetic disorders ; Genetic research ; Genetics ; Genetics(clinical) ; Homozygote ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Keratinocytes ; Keratosis - genetics ; Male ; Middle Aged ; Mutation ; Nail Diseases - genetics ; Pedigree ; Proteases ; Proteins ; Report ; Research ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Skin - pathology ; Skin Diseases - genetics
ispartofAmerican journal of human genetics, 2015-03-05, Vol.96 (3), p.440-447
rights
02015 The American Society of Human Genetics
1Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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42015 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2015 The American Society of Human Genetics
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1Zhao, Jiahui
2Nitoiu, Daniela
3Scott, Claire A
4Plagnol, Vincent
5Smith, Frances J.D
6Wilson, Neil J
7Cole, Christian
8Schwartz, Mary E
9McLean, W.H. Irwin
10Wang, Huijun
11Feng, Cheng
12Duo, Lina
13Zhou, Eray Yihui
14Ren, Yali
15Dai, Lanlan
16Chen, Yulan
17Zhang, Jianguo
18Xu, Xun
19O’Toole, Edel A
20Kelsell, David P
21Yang, Yong
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0Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads
1American journal of human genetics
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descriptionCalpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.
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28Report
29Research
30RNA, Small Interfering - genetics
31RNA, Small Interfering - metabolism
32Skin - pathology
33Skin Diseases - genetics
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8Schwartz, Mary E
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10Wang, Huijun
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13Zhou, Eray Yihui
14Ren, Yali
15Dai, Lanlan
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titleLoss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads
authorLin, Zhimiao ; Zhao, Jiahui ; Nitoiu, Daniela ; Scott, Claire A ; Plagnol, Vincent ; Smith, Frances J.D ; Wilson, Neil J ; Cole, Christian ; Schwartz, Mary E ; McLean, W.H. Irwin ; Wang, Huijun ; Feng, Cheng ; Duo, Lina ; Zhou, Eray Yihui ; Ren, Yali ; Dai, Lanlan ; Chen, Yulan ; Zhang, Jianguo ; Xu, Xun ; O’Toole, Edel A ; Kelsell, David P ; Yang, Yong
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1Apoptosis - genetics
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7Chromatin
8Epidermis - metabolism
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8Schwartz, Mary E
9McLean, W.H. Irwin
10Wang, Huijun
11Feng, Cheng
12Duo, Lina
13Zhou, Eray Yihui
14Ren, Yali
15Dai, Lanlan
16Chen, Yulan
17Zhang, Jianguo
18Xu, Xun
19O’Toole, Edel A
20Kelsell, David P
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1Zhao, Jiahui
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7Cole, Christian
8Schwartz, Mary E
9McLean, W.H. Irwin
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13Zhou, Eray Yihui
14Ren, Yali
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notes
0These authors contributed equally to this work and are joint first authors
1These authors contributed equally to this work and are joint senior authors
abstractCalpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.
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pmid25683118
doi10.1016/j.ajhg.2014.12.026
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