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 - 2019/7/1
Y1 - 2019/7/1
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
AN - SCOPUS:85056467388
SN - 1098-3600
VL - 21
SP - 1559
EP - 1567
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -