Mutation of melanosome protein RAB38 in chocolate mice.
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.
Loftus
Stacie K
SK
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Larson
Denise M
DM
Baxter
Laura L
LL
Antonellis
Anthony
A
Chen
Yidong
Y
Wu
Xufeng
X
Jiang
Yuan
Y
Bittner
Michael
M
Hammer
John A
JA
Pavan
William J
WJ
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002874:Chromosome Mapping; D020869:Gene Expression Profiling; D006801:Humans; D008544:Melanocytes / Q000502:physiology; D020460:Melanosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases; D010859:Pigmentation Disorders / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology
D008562:Membrane Glycoproteins; D010088:Oxidoreductases; C489799:TYRP1 protein, human; C079621:Tyrp1 protein, mouse; C412058:RAB38 protein, human; C498786:Rab38 protein, mouse; D020691:rab GTP-Binding Proteins