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.
N1 - Funding Information:
We are grateful to the family who participated in this study. This study was funded by the Dutch Organization for Scientific Research (NWO-ALW, project number 821.02.013). E.v.d.B. was funded by a Veni grant from the Dutch Organization for Scientific Research (project number 91616054). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018, The Author(s).
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 - proteases
KW - hair follicle
KW - 3D-reconstructed epidermis
KW - skin barrier
KW - OF-FUNCTION MUTATIONS
KW - CATHEPSIN-L
KW - PROTEINASE-INHIBITOR
KW - HAIR FOLLICLE
KW - EPIDERMAL-KERATINOCYTES
KW - EXFOLIATIVE ICHTHYOSIS
KW - TARGET
KW - DIFFERENTIATION
KW - FILAGGRIN
KW - MORPHOGENESIS
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 -