Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads. Lin, Z., Zhao, J., Nitoiu, D., Scott, C. A., Plagnol, V., Smith, F. J. D., Wilson, N. J., Cole, C., Schwartz, M. E., McLean, W. H. I., Wang, H., Feng, C., Duo, L., Zhou, E. Y., Ren, Y., Dai, L., Chen, Y., Zhang, J., Xu, X., O’Toole, E. A., Kelsell, D. P., & Yang, Y. The American Journal of Human Genetics, 96(3):440–447, May, 2015.
Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads [link]Paper  doi  abstract   bibtex   
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\textbackslashtextgreaterT, 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.
@article{lin_loss--function_2015,
	title = {Loss-of-{Function} {Mutations} in {CAST} {Cause} {Peeling} {Skin}, {Leukonychia}, {Acral} {Punctate} {Keratoses}, {Cheilitis}, and {Knuckle} {Pads}},
	volume = {96},
	issn = {0002-9297},
	url = {http://www.cell.com/article/S0002929715000051/abstract},
	doi = {10.1016/j.ajhg.2014.12.026},
	abstract = {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{\textbackslash}textgreaterT, 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 = {English},
	number = {3},
	urldate = {2015-09-22},
	journal = {The American Journal of Human Genetics},
	author = {Lin, Zhimiao and Zhao, Jiahui and Nitoiu, Daniela and Scott, Claire A. and Plagnol, Vincent and Smith, Frances J. D. and Wilson, Neil J. and Cole, Christian and Schwartz, Mary E. and McLean, W. H. Irwin and Wang, Huijun and Feng, Cheng and Duo, Lina and Zhou, Eray Yihui and Ren, Yali and Dai, Lanlan and Chen, Yulan and Zhang, Jianguo and Xu, Xun and O’Toole, Edel A. and Kelsell, David P. and Yang, Yong},
	month = may,
	year = {2015},
	pmid = {25683118},
	keywords = {WES, exome, mine},
	pages = {440--447}
}

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