PUBLICATION
Evolutionary distinct roles of γ-secretase subunit nicastrin in zebrafish and humans
- Authors
- Hermasch, M.A., Janning, H., Perera, R.P., Schnabel, V., Rostam, N., Ramos-Gomes, F., Muschalek, W., Bennemann, A., Alves, F., Ralser, D.J., Betz, R.C., Schön, M.P., Dosch, R., Frank, J.
- ID
- ZDB-PUB-220113-5
- Date
- 2022
- Source
- Journal of dermatological science 105(2): 80-87 (Journal)
- Registered Authors
- Dosch, Roland
- Keywords
- Dowling-Degos disease, Gamma-secretase, Nicastrin, Pigmentation, Zebrafish
- MeSH Terms
-
- Amyloid Precursor Protein Secretases/genetics
- Amyloid Precursor Protein Secretases/metabolism*
- Animals
- Hidradenitis Suppurativa/genetics
- Humans
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/metabolism*
- Zebrafish
- PubMed
- 35016821 Full text @ J. Dermatol. Sci.
Citation
Hermasch, M.A., Janning, H., Perera, R.P., Schnabel, V., Rostam, N., Ramos-Gomes, F., Muschalek, W., Bennemann, A., Alves, F., Ralser, D.J., Betz, R.C., Schön, M.P., Dosch, R., Frank, J. (2022) Evolutionary distinct roles of γ-secretase subunit nicastrin in zebrafish and humans. Journal of dermatological science. 105(2):80-87.
Abstract
Background Mutations in the genes that encode the human γ-secretase subunits Presenilin-1, Presenilin Enhancer Protein 2, and Nicastrin (NCSTN) are associated with familial hidradenitis suppurativa (HS); and, regarding Presenilin Enhancer Protein 2, also with comorbidity for the hereditary pigmentation disorder Dowling-Degos disease.
Objective Here, the consequences of targeted inactivation of ncstn, the zebrafish homologue of human NCSTN, were studied.
Methods After morpholino (MO)-mediated ncstn-knockdown, the possibilities of phenotype rescue through co-injection of ncstn-MO with wildtype zebrafish ncstn or human NCSTN mRNA were investigated. Further, the effects of the co-injection of a human missense, nonsense, splice-site, and frameshift mutation were studied.
Results MO-mediated ncstn-knockdown resulted in a significant reduction in melanophore morphology, size and number; and alterations in their patterns of migration and distribution. This phenotype was rescued by co-injection of zebrafish ncstn RNA, human NCSTN RNA, or a construct encoding the human NCSTN missense mutation p.P211R.
Conclusion Human NCSTN mutations encoding null alleles confer loss-of-function regarding pigmentation homeostasis in zebrafisch. In contrast, the human missense mutation p.P211R was less harmful, asserting sufficient residual ncstn activity to maintain pigmentation in zebrafish. Since fish lack the anatomical structures affected by HS, our data suggest that the zebrafish ncstn gene and the human NCSTN gene have probably acquired different functions during evolution. In fish, one major role of ncstn is the maintenance of pigmentation homeostasis. In contrast, one of the roles of NCSTN in humans is the prevention of inflammatory processes in the adnexal structures of the skin, as seen in familial HS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping