Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin

Ellen H J van den Bogaard; Michel van Geel; Ivonne M J J van Vlijmen-Willems; Patrick A M Jansen; Malou Peppelman; Piet E J van Erp; Selma Atalay; Hanka Venselaar; Marleen E H Simon; Marieke Joosten; Joost Schalkwijk; Patrick L J M Zeeuwen

doi:10.1038/s41436-018-0355-3

Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin

Ellen H J van den Bogaard
, Michel van Geel
, Ivonne M J J van Vlijmen-Willems
, Patrick A M Jansen
, Malou Peppelman
, Piet E J van Erp
, Selma Atalay
, Hanka Venselaar
, Marleen E H Simon
, Marieke Joosten
, Joost Schalkwijk
, Patrick L J M Zeeuwen

Section Clinical Genetics

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

PURPOSE: We aimed to assess the biological and clinical significance of the human cysteine protease inhibitor cystatin M/E, encoded by the CTS6 gene, in diseases of human hair and skin.

METHODS: Exome and Sanger sequencing was performed to reveal the genetic cause in two related patients with hypotrichosis. Immunohistochemical, biophysical, and biochemical measurements were performed on patient skin and 3D-reconstructed skin from patient-derived keratinocytes.

RESULTS: We identified a homozygous variant c.361C>T (p.Gln121*), resulting in a premature stop codon in exon 2 of CST6 associated with hypotrichosis, eczema, blepharitis, photophobia and impaired sweating. Enzyme assays using recombinant mutant cystatin M/E protein, generated by site-directed mutagenesis, revealed that this p.Gln121* variant was unable to inhibit any of its three target proteases (legumain and cathepsins L and V). Three-dimensional protein structure prediction confirmed the disturbance of the protease/inhibitor binding sites of legumain and cathepsins L and V in the p.Gln121* variant.

CONCLUSION: The herein characterized autosomal recessive hypotrichosis syndrome indicates an important role of human cystatin M/E in epidermal homeostasis and hair follicle morphogenesis.

Original language	English
Pages (from-to)	1559-1567
Number of pages	9
Journal	Genetics in Medicine
Volume	21
Issue number	7
DOIs	https://doi.org/10.1038/s41436-018-0355-3
Publication status	Published - Jul 2019

Keywords

3D-reconstructed epidermis
hair follicle
proteases
skin barrier

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van den Bogaard, E. H. J., van Geel, M., van Vlijmen-Willems, I. M. J. J., Jansen, P. A. M., Peppelman, M., van Erp, P. E. J., Atalay, S., Venselaar, H., Simon, M. E. H., Joosten, M., Schalkwijk, J., & Zeeuwen, P. L. J. M. (2019). Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin. Genetics in Medicine, 21(7), 1559-1567. https://doi.org/10.1038/s41436-018-0355-3

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title = "Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin",

abstract = "PURPOSE: We aimed to assess the biological and clinical significance of the human cysteine protease inhibitor cystatin M/E, encoded by the CTS6 gene, in diseases of human hair and skin.METHODS: Exome and Sanger sequencing was performed to reveal the genetic cause in two related patients with hypotrichosis. Immunohistochemical, biophysical, and biochemical measurements were performed on patient skin and 3D-reconstructed skin from patient-derived keratinocytes.RESULTS: We identified a homozygous variant c.361C>T (p.Gln121*), resulting in a premature stop codon in exon 2 of CST6 associated with hypotrichosis, eczema, blepharitis, photophobia and impaired sweating. Enzyme assays using recombinant mutant cystatin M/E protein, generated by site-directed mutagenesis, revealed that this p.Gln121* variant was unable to inhibit any of its three target proteases (legumain and cathepsins L and V). Three-dimensional protein structure prediction confirmed the disturbance of the protease/inhibitor binding sites of legumain and cathepsins L and V in the p.Gln121* variant.CONCLUSION: The herein characterized autosomal recessive hypotrichosis syndrome indicates an important role of human cystatin M/E in epidermal homeostasis and hair follicle morphogenesis.",

keywords = "3D-reconstructed epidermis, hair follicle, proteases, skin barrier",

author = "\{van den Bogaard\}, \{Ellen H J\} and \{van Geel\}, Michel and \{van Vlijmen-Willems\}, \{Ivonne M J J\} and Jansen, \{Patrick A M\} and Malou Peppelman and \{van Erp\}, \{Piet E J\} and Selma Atalay and Hanka Venselaar and Simon, \{Marleen E H\} and Marieke Joosten and Joost Schalkwijk and Zeeuwen, \{Patrick L J M\}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2019",

month = jul,

doi = "10.1038/s41436-018-0355-3",

language = "English",

volume = "21",

pages = "1559--1567",

journal = "Genetics in Medicine",

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van den Bogaard, EHJ, van Geel, M, van Vlijmen-Willems, IMJJ, Jansen, PAM, Peppelman, M, van Erp, PEJ, Atalay, S, Venselaar, H, Simon, MEH, Joosten, M, Schalkwijk, J & Zeeuwen, PLJM 2019, 'Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin', Genetics in Medicine, vol. 21, no. 7, pp. 1559-1567. https://doi.org/10.1038/s41436-018-0355-3

TY - JOUR

T1 - Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin

AU - van den Bogaard, Ellen H J

AU - van Geel, Michel

AU - van Vlijmen-Willems, Ivonne M J J

AU - Jansen, Patrick A M

AU - Peppelman, Malou

AU - van Erp, Piet E J

AU - Atalay, Selma

AU - Venselaar, Hanka

AU - Simon, Marleen E H

AU - Joosten, Marieke

AU - Schalkwijk, Joost

AU - Zeeuwen, Patrick L J M

PY - 2019/7

Y1 - 2019/7

N2 - PURPOSE: We aimed to assess the biological and clinical significance of the human cysteine protease inhibitor cystatin M/E, encoded by the CTS6 gene, in diseases of human hair and skin.METHODS: Exome and Sanger sequencing was performed to reveal the genetic cause in two related patients with hypotrichosis. Immunohistochemical, biophysical, and biochemical measurements were performed on patient skin and 3D-reconstructed skin from patient-derived keratinocytes.RESULTS: We identified a homozygous variant c.361C>T (p.Gln121*), resulting in a premature stop codon in exon 2 of CST6 associated with hypotrichosis, eczema, blepharitis, photophobia and impaired sweating. Enzyme assays using recombinant mutant cystatin M/E protein, generated by site-directed mutagenesis, revealed that this p.Gln121* variant was unable to inhibit any of its three target proteases (legumain and cathepsins L and V). Three-dimensional protein structure prediction confirmed the disturbance of the protease/inhibitor binding sites of legumain and cathepsins L and V in the p.Gln121* variant.CONCLUSION: The herein characterized autosomal recessive hypotrichosis syndrome indicates an important role of human cystatin M/E in epidermal homeostasis and hair follicle morphogenesis.

AB - PURPOSE: We aimed to assess the biological and clinical significance of the human cysteine protease inhibitor cystatin M/E, encoded by the CTS6 gene, in diseases of human hair and skin.METHODS: Exome and Sanger sequencing was performed to reveal the genetic cause in two related patients with hypotrichosis. Immunohistochemical, biophysical, and biochemical measurements were performed on patient skin and 3D-reconstructed skin from patient-derived keratinocytes.RESULTS: We identified a homozygous variant c.361C>T (p.Gln121*), resulting in a premature stop codon in exon 2 of CST6 associated with hypotrichosis, eczema, blepharitis, photophobia and impaired sweating. Enzyme assays using recombinant mutant cystatin M/E protein, generated by site-directed mutagenesis, revealed that this p.Gln121* variant was unable to inhibit any of its three target proteases (legumain and cathepsins L and V). Three-dimensional protein structure prediction confirmed the disturbance of the protease/inhibitor binding sites of legumain and cathepsins L and V in the p.Gln121* variant.CONCLUSION: The herein characterized autosomal recessive hypotrichosis syndrome indicates an important role of human cystatin M/E in epidermal homeostasis and hair follicle morphogenesis.

KW - 3D-reconstructed epidermis

KW - hair follicle

KW - proteases

KW - skin barrier

U2 - 10.1038/s41436-018-0355-3

DO - 10.1038/s41436-018-0355-3

M3 - Article

C2 - 30425301

SN - 1098-3600

VL - 21

SP - 1559

EP - 1567

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 7

ER -

Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin

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