Mutation of melanosome protein RAB38 in chocolate mice

doi:10.1073/pnas.072087599

Mutation of melanosome protein RAB38 in chocolate mice

^*Genetic Disease Research Branch and ^‡Cancer Genetics Branch, National Human Genome Research Institute, ^§Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and ^†Graduate Genetics Program, George Washington University, Washington, DC 20052

Communicated by Francis S. Collins, National Institutes of Health, Bethesda, MD (received for review January 2, 2002)

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.

Footnotes

↵ ¶ To whom reprint requests should be addressed. E-mail: bpavan{at}nhgri.nih.gov.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. AY062237 (mRAB38), AF448441 (mRAB38 exon 1), AF448442 (exon 2), and AF448443 (exon 3)].
Abbreviations:

OCA,

oculocutaneous albinism;

CHS,

Chediak–Higashi syndrome;

HPS,

Hermansky-Pudlak syndrome;

cht,

chocolate;

GFP,

green fluorescent protein;

RPE,

retinal pigmented epithelium;

TYRP1,

tyrosinase-related protein 1