Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Genet Med. 2019 Jul;21(7):1559-1567. doi: 10.1038/s41436-018-0355-3. Epub 2018 Nov 14.

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

Author information

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. Patrick.Zeeuwen@radboudumc.nl.

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

PMID:
30425301
DOI:
10.1038/s41436-018-0355-3

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center