Evolutionary distinct roles of γ-secretase subunit nicastrin in zebrafish and humans.

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.

• Authors: Matthias Andreas Hermasch, Helena Janning, Roshan Priyarangana Perera, Viktor Schnabel, Nadia Rostam, Fernanda Ramos-Gomes, Wiebke Muschalek, Anette Bennemann, Frauke Alves, Damian Johannes Ralser, Regina Christine Betz, Michael Peter Schön, Roland Dosch, Jorge Frank
• Journal: Journal of dermatological science (J Dermatol Sci) Vol. 105 Issue 2 Pg. 80-87 (Feb 2022) ISSN: 1873-569X [Electronic] Netherlands
• PMID: 35016821 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Chemical References

• Membrane Glycoproteins
• nicastrin protein
• Amyloid Precursor Protein Secretases

Topics

• Amyloid Precursor Protein Secretases (genetics, metabolism)
• Animals
• Hidradenitis Suppurativa (genetics)
• Humans
• Membrane Glycoproteins (genetics, metabolism)
• Zebrafish