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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)


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 languageEnglish
Pages (from-to)1559-1567
Number of pages9
JournalGenetics in Medicine
Issue number7
Publication statusPublished - 1 Jul 2019
Externally publishedYes


  • 3D-reconstructed epidermis
  • hair follicle
  • proteases
  • skin barrier


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