The DOI matches its Crossref record.
Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin
Open accessAbstract
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.
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Variants of TSPEAR, HOXC13, or CST6 have been shown to underlie new forms of ED.
“To be mentioned here, for example, variants of TSPEAR [47,48], HOXC13 [49] or CST6 [50] have been shown to underlie new forms of ED.”
From Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update (2022) · cites this paper as [50]
The Introduction reports that a CST6 loss-of-function variant causes a novel autosomal recessive hypotrichosis syndrome, and the Results describe affected family members with dry skin. The paper does not identify the syndrome as ectodermal dysplasia (ED); the Discussion classifies it as a heritable hair disease. This citation supports the CST6 link to a new syndrome, but not its stated ED classification. (LLM, conf=0.83)
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Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update
Peschel, N., Wright, J. T., Koster, M. I., Clarke, A. J., Tadini, G., Fete, M., Hadj-Rabia, S., Sybert, V. P., Norderyd, J., Maier-Wohlfart, S., et al. (2022) · Genes · doi:10.3390/genes13122327 · Cited by 60
Metadata
- Authors
- van den Bogaard, E. H. J., van Geel, M., van Vlijmen-Willems, I. M. J. J., Jansen, P. A. M., Peppelman, M., van Erp, P. E. J., Atalay, S., Venselaar, H., Simon, M. E. H., Joosten, M., Schalkwijk, J., & Zeeuwen, P. L. J. M.
- Affiliations
- Radboud University Nijmegen (NL)
- Maastricht University Medical Centre (NL)
- University Medical Center Utrecht (NL)
- Erasmus MC (NL)
- Corresponding author
- Zeeuwen, Patrick L.J.M.
- ORCID
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 21
- Issue
- 7
- Pages
- 1559-1567
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC6752276
- OpenAlex
- W2901364936
- Cited by
- 18
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 1
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Socio-Environmental Systems Modeling (acceptedVersion, cc-by-nc-nd)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, cc-by-nc-nd)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-nd)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (821.02.013)
- Topics
- Health Sciences › Medicine › Dermatology › Hair Growth and Disorders
- Health Sciences › Medicine › Dermatology › Genetic and rare skin diseases.
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- hypotrichosis, dry skin, atopic dermatitis, blepharitis, premature stop codon, cysteine protease inhibitors, legumain, cathepsin L, cathepsin V, protease inhibition, hair follicle morphogenesis, epidermal homeostasis, autosomal recessive syndrome
- MeSH terms
- Exome Sequencing, Loss of Function Mutation, Alopecia, Child, Consanguinity, Female, Humans, Male, Skin Diseases, Cysteine Proteinase Inhibitors, Cystatin M
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