Griscelli syndrome (GS) patients and the corresponding mouse model
ashen
exhibit defects mainly in two types of lysosome-related organelles, melanosomes in melanocytes and lytic granules in CTLs. ...This disease is caused by loss-of-function mutations in
RAB27A
, which encodes 1 of the 60 known Rab GTPases, critical regulators of vesicular transport. Here we present evidence that Rab27a function can be compensated by a closely related protein, Rab27b. Rab27b is expressed in platelets and other tissues but not in melanocytes or CTLs. Morphological and functional tests in platelets derived from
ashen
mice are all within normal limits. Both Rab27a and Rab27b are found associated with the limiting membrane of platelet-dense granules and to a lesser degree with α-granules. Ubiquitous transgenic expression of Rab27a or Rab27b rescues
ashen
coat color, and melanocytes derived from transgenic mice exhibit widespread peripheral distribution of melanosomes instead of the perinuclear clumping observed in
ashen
melanocytes. Finally, transient expression in
ashen
melanocytes of Rab27a or Rab27b, but not other Rab’s, restores peripheral distribution of melanosomes. Our data suggest that Rab27b is functionally redundant with Rab27a and that the pathogenesis of GS is determined by the relative expression of Rab27a and Rab27b in specialized cell types.
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