Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome.
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 alpha-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.
Cell and Molecular Biology, Division of Biomedical Sciences, Faculty of Medicine, Imperial College, London, United Kingdom.
Duarte C
DC
Barral
José S
JS
Ramalho
Ross
R
Anders
Alistair N
AN
Hume
Holly J
HJ
Knapton
Tanya
T
Tolmachova
Lucy M
LM
Collinson
David
D
Goulding
Kalwant S
KS
Authi
Miguel C
MC
Seabra
D000818:Animals; D001792:Blood Platelets / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D015870:Gene Expression; D015616:Histiocytosis, Non-Langerhans-Cell / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017496:Hypopigmentation / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008544:Melanocytes / Q000473:pathology / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D013577:Syndrome; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D000075745:rab27 GTP-Binding Proteins
D000075745:rab27 GTP-Binding Proteins; C512958:Rab27b protein, mouse; C066694:RAB27A protein, human; C512960:Rab27B protein, human; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins