title: A mutation in Rab27a causes the vesicle transport defects observed in ashen mice.
abstract: The dilute (d), leaden (ln), and ashen (ash) mutations provide a unique model system for studying vesicle transport in mammals. All three mutations produce a lightened coat color because of defects in pigment granule transport. In addition, all three mutations are suppressed by the semidominant dilute-suppressor (dsu), providing genetic evidence that these mutations function in the same or overlapping transport pathways. Previous studies showed that d encodes a major vesicle transport motor, myosin-VA, which is mutated in Griscelli syndrome patients. Here, using positional cloning and bacterial artificial chromosome rescue, we show that ash encodes Rab27a. Rab GTPases represent the largest branch of the p21 Ras superfamily and are recognized as key players in vesicular transport and organelle dynamics in eukaryotic cells. We also show that ash mice have platelet defects resulting in increased bleeding times and a reduction in the number of platelet dense granules. These defects have not been reported for d and ln mice. Collectively, our studies identify Rab27a as a critical gene for organelle-specific protein trafficking in melanocytes and platelets and suggest that Rab27a functions in both MyoVa dependent and independent pathways.
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Wilson
authors.forename: R
authors.initials: R
authors.lastname: Yip
authors.forename: D A
authors.initials: DA
authors.lastname: Swing
authors.forename: T N
authors.initials: TN
authors.lastname: O'Sullivan
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: E K
authors.initials: EK
authors.lastname: Novak
authors.forename: R T
authors.initials: RT
authors.lastname: Swank
authors.forename: L B
authors.initials: LB
authors.lastname: Russell
authors.forename: N G
authors.initials: NG
authors.lastname: Copeland
authors.forename: N A
authors.initials: NA
authors.lastname: Jenkins
mesh_terms: D016115:Albinism, Oculocutaneous; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D001792:Blood Platelets / Q000473:pathology; D002874:Chromosome Mapping; D003594:Cytoplasmic Granules / Q000469:parasitology; D004195:Disease Models, Animal; D015723:Gene Library; D005816:Genetic Complementation Test; D006200:Hair Color / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D009115:Muridae; D018995:Myosin Heavy Chains; D024701:Myosin Type V; D011485:Protein Binding; D012326:RNA Splicing; D012867:Skin / Q000166:cytology; D013577:Syndrome; D020691:rab GTP-Binding Proteins / Q000235:genetics*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D007381:Intermediate Filament Proteins; C513082:Myo5a protein, mouse; D000075745:rab27 GTP-Binding Proteins; D024701:Myosin Type V; C512962:Rab27a protein, mouse; D018995:Myosin Heavy Chains; D020691:rab GTP-Binding Proteins