Why Albinism Impairs Eyesight

Science Signaling  07 Oct 2008:
Vol. 1, Issue 40, pp. ec345
DOI: 10.1126/scisignal.140ec345

Albinism is a disease characterized by loss of pigmentation and, frequently, impaired vision. Ocular albinism, which affects only the ocular tissues, has been linked to the Oa1 gene, which encodes OA1, an orphan G protein-coupled receptor (GPCR) for which the endogenous ligand has not been reported. Because there has been controversy about the function of OA1 due to its presence on internal membranes in cultured cells, Lopez et al. performed in situ surface biotinylation experiments with human eyes. They found that a fraction of OA1 was present on the apical surface of cells in the retinal pigmented epithelium (RPE). However, when these cells were cultured in normal cell culture medium, which contains high concentrations of tyrosine, OA1 was localized intracellularly. When the RPE or cells transfected with OA1 were cultured in medium lacking tyrosine or with low concentrations (1 μM) of tyrosine, then OA1 was detected at the cell surface. Tyrosine is metabolized to L-DOPA during melanin synthesis; L-DOPA is also an intermediate in the synthesis of the neurotransmitter dopamine. Addition of L-DOPA, but not tyrosine or dopamine, to the culture medium stimulated a calcium signal in RPE cells or cells transfected with OA1, and L-DOPA exhibited saturable binding to OA1-expressing cells. Furthermore, cultured RPE cells, in which tyrosinase was inhibited to block endogenous production of L-DOPA and melanin, exhibited decreased secretion of a trophic factor called PEDF (pigment epithelium-derived factor). Secretion of PEDF was restored if the medium was supplemented with L-DOPA. This apparent autocrine signaling pathway controlling PEDF secretion may explain why mutations in the Oa1 gene lead to ocular albinism and visual impairment.

V. M. Lopez, C. L. Decatur, W. D. Stamer, R. M. Lynch, B. S. McKay, L-DOPA is an endogenous ligand for AO1. PLoS Biol. 6, e236 (2008). [PubMed]