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

5 Citations (Web of Science)

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 languageEnglish
Pages (from-to)1559-1567
Number of pages9
JournalGenetics in Medicine
Volume21
Issue number7
DOIs
Publication statusPublished - Jul 2019

Keywords

  • proteases
  • hair follicle
  • 3D-reconstructed epidermis
  • skin barrier
  • OF-FUNCTION MUTATIONS
  • CATHEPSIN-L
  • PROTEINASE-INHIBITOR
  • HAIR FOLLICLE
  • EPIDERMAL-KERATINOCYTES
  • EXFOLIATIVE ICHTHYOSIS
  • TARGET
  • DIFFERENTIATION
  • FILAGGRIN
  • MORPHOGENESIS

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