2. Academic Validation
  3. Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin

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

  • Genet Med. 2019 Jul;21(7):1559-1567. doi: 10.1038/s41436-018-0355-3.
Ellen H J van den Bogaard 1,  Michel van Geel 2 3 4,  Ivonne M J J van Vlijmen-Willems 1,  Patrick A M Jansen 1,  Malou Peppelman 1,  Piet E J van Erp 1,  Selma Atalay 1,  Hanka Venselaar 5,  Marleen E H Simon 6,  Marieke Joosten 7,  Joost Schalkwijk 1,  Patrick L J M Zeeuwen 8
Affiliations

Affiliations

  • 1 Department of Dermatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen Medical Center (Radboudumc), Nijmegen, The Netherlands.
  • 2 Department of Dermatology, Maastricht University Medical Centre, Maastricht, The Netherlands.
  • 3 Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
  • 4 GROW Research Institute for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
  • 5 Center for Molecular and Biomolecular Informatics, RIMLS, Radboudumc, Nijmegen, The Netherlands.
  • 6 Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
  • 7 Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
  • 8 Department of Dermatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen Medical Center (Radboudumc), Nijmegen, The Netherlands. [email protected].
PMID: 30425301 DOI: 10.1038/s41436-018-0355-3
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.

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