Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: Consequences of disease-causing mutations and implications for melanosome biogenesis

To investigate the function of ocular albinism type 1 (OA1), the gene respo nsible for X-linked ocular albinism, we employed a construct containing mur ine Oa1 fused to green fluorescent protein (GFP) in a heterologous COS cell expression system. The cellular distribution of wildtype (WT) Oa1 protein and Oa1 proteins reflecting mutations causing X-linked ocular albinism were examined. Comparison with different organelle markers revealed that Oa1-GF P localized to the late endolysosomal compartments. Some Oa1 mutant protein s failed to exit the endoplasmic reticulum (ER) (Class I mutants), while ot her mutants partially (Class II mutants) or fully (Class III mutants) exite d the ER and trafficked to endolysosomal compartments. We observed that exp ression of WT Oa1-GFP in COS cells caused an apparent enlargement of late e ndosomes and a redistribution of the mannose-6-phosphate receptor (M6PR). N one of the mutants displayed the full range of effects on the redistributio n of M6PR exhibited by WT Oa1. The effects of Oa1 on late endosome structur e and content are thus likely to reflect an important biological property o f Oa1. We propose that OA1 is involved in reorganizing the endolysosomal co mpartment as a necessary step in ocular melanosome biogenesis.