A mutation in Rab27a causes the vesicle transport defects observed in ashen mice

The dilute (d), leaden (ln), and ashen (ash) mutations provide a unique mod el system for studying vesicle transport in mammals. All three mutations pr oduce a lightened coat color because of defects in pigment granule transpor t. In addition, all three mutations are suppressed by the semidominant dilu te-suppressor (dsu), providing genetic evidence that these mutations functi on in the same or overlapping transport pathways, Previous studies showed t hat d encodes a major vesicle transport motor, myosin-VA, which is mutated in Griscelli syndrome patients. Here, using positional cloning and bacteria l artificial chromosome rescue, we show that ash encodes Rab27a, Rab GTPase s represent the largest branch of the p21 Ras superfamily and are recognize d as key players in vesicular transport and organelle dynamics in eukaryoti c cells. We also show that ash mice have platelet defects resulting in incr eased bleeding times and a reduction in the number of platelet dense granul es. These defects have not been reported for d and In mice. Collectively, o ur studies identify Rab27a as a critical gene for organelle-specific protei n trafficking in melanocytes and platelets and suggest that Rab27a function s in both MyoVa dependent and independent pathways.