Mutation of melanosome protein RAB38 in chocolate mice

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Abstract
Mutations of genes needed for melanocyte function can result in oculocutaneous albinism. Examination of similarities in human gene expression patterns by using microarray analysis reveals that RAB38 , a small GTP binding protein, demonstrates a similar expression profile to melanocytic genes. Comparative genomic analysis localizes human RAB38 to the mouse chocolate ( cht ) locus. A G146T mutation occurs in the conserved GTP binding domain of RAB38 in cht mice. Rab38 cht /Rab38 cht mice exhibit a brown coat similar in color to mice with a mutation in tyrosinase-related protein 1 ( Tyrp1 ), a mouse model for oculocutaneous albinism. The targeting of TYRP1 protein to the melanosome is impaired in Rab38 cht /Rab38 cht melanocytes. These observations, and the fact that green fluorescent protein-tagged RAB38 colocalizes with end-stage melanosomes in wild-type melanocytes, suggest that RAB38 plays a role in the sorting of TYRP1. This study demonstrates the utility of expression profile analysis to identify mammalian disease genes.