Slc45a2 and V-ATPase are regulators of melanosomal pH homeostasis in zebrafish, providing a mechanism for human pigment evolution and disease

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We present here the positional cloning of theDanio rerio albinomutant and show that the affected gene encodes Slc45a2. The human orthologous gene has previously been shown to be involved in human skin color variation, and mutations therein have been implicated in the disease OCA4. Through ultrastructural analysis of the melanosomes inalbinoalleles as well as the tyrosinase-deficient mutantsandy, we add new insights into the role ofSlc45a2in the production of melanin. To gain further understanding of the role ofSlc45a2and its possible interactions with other proteins involved in melanization, we further analyzed the role of the V-ATPase as a melanosomal acidifier. We show that it is possible to rescue the melanization potential of thealbinomelanosomes through genetic and chemical inhibition of V-ATPase, thereby increasing internal melanosome pH.

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