Does Nicastrin Deficiency Cause Melanocytotoxicity in Human Skin as in the Fish Counterpart?

The document from May 1, 2021, explores the role of nicastrin deficiency in causing melanocytotoxicity, which may be linked to skin depigmentation diseases such as vitiligo, hidradenitis suppurativa, and Dowling-Degos disease. It builds on the findings of Hsu et al. (2020) that nicastrin deficiency in zebrafish leads to melanosome defects and melanophore cell death, and defends the relevance of these findings to human skin conditions by showing that nicastrin heterozygotes in humans exhibit related skin disorders. The paper suggests that melanocytotoxicity could lead to keratinocyte hyperproliferation and hyperkeratosis, and that increased melanosome production and transport to keratinocytes could result in hyperpigmented and damaged skin. The use of tyrosinase inhibitors in nicastrin mutants is proposed to prevent pigment loss and mitochondrial swelling, indicating the potential toxicity of these inhibitors to cells containing tyrosinase. The document concludes that further investigation is needed to understand the intracellular localization of tyrosinase and its role in cytotoxicity in nicastrin mutants, and acknowledges funding from Taiwanese institutions.