Drosophila orthologues of oculocutaneous albinism-associated genes regulate sleep and circadian rhythm via visual neurotransmission

Melanin is a pigment found in the skin and cuticle of animals. Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders defined by reduced melanin in skin and eyes, and is associated with visual defects such as foveal hypoplasia and infantile nystagmus. Sleep disturbance has been documented in children with OCA, and oca2 loss-of-function in cavefish causes constitutive sleep loss, indicating a sleep regulatory function of OCA-associated genes in the visual system. To test potential roles of OCA-associated genes in regulating sleep and vision through evolutionarily conserved mechanisms, we used Drosophila melanogaster, a high-throughput phenotyping system to screen sleep and visual phenotypes for genetic mutants of OCA-associated genes. Among the OCA-associated genes, bidirectional DRSC Integrative Ortholog Prediction Tool identified Drosophila orthologues for OCA2, SLC45A2, SLC24A5 and LRMDA. RNAi-mediated knockdown in developing Drosophila eye tissue identified the OCA2 orthologues hoe1, hoe2, and the SLC45A2 orthologue lovit as candidate gene required for normal sleep. Moreover, hoe1, hoe2 and lovit1 null alleles reduced sleep and circadian rhythmicity, and showed altered photoreceptor neurotransmission. Collectively the data indicate evolutionarily conserved neuronal function of OCA2 and SLC45A2 orthologues that regulates sleep and photoreceptor neurotransmission. Author summaryOculocutaneous albinism (OCA) is a pigmentation disorder of the skin and eyes accompanied by reduced visual acuity and nystagmus. Children with albinism also report sleep disturbance, and the mechanism is unclear. We tested whether genes mutated in albinism regulate sleep in the fruit fly Drosophila melanogaster, an organism that has a divergent melanin synthesis pathway and lacks tyrosinase, the principal pigmentation enzyme in mammals. We screened fly orthologues of seven human OCA-associated genes and identified two that regulate sleep: the OCA2 orthologues hoe1 and hoe2, and the SLC45A2 orthologue lovit. Mutants of these genes show reduced sleep and circadian rhythmicity; electrical recordings show that photoreceptors fail to signal normally to downstream neurons, placing the sleep defect within a defined visual circuit. Because none of the above mutation cause pigmentation defect, our finding shows that OCA2 and SLC45A2 have a neuronal function that is separate from pigment synthesis. Pigment synthesis cells and neurons share a common embryonic origin, which may explain how the same transporter genes came to function in both cell types, and the data are consistent with the proposal that this pleiotropic neuronal function underlies the sleep and vision symptoms in albinism.