Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis.
Few molecular events important to platelet biogenesis have been identified. Mice homozygous for the spontaneous, recessive mutation gunmetal (gm) have prolonged bleeding, thrombocytopenia, and reduced platelet alpha- and delta-granule contents. Here we show by positional cloning that gm results from a G-->A substitution mutation in a splice acceptor site within the alpha-subunit of Rab geranylgeranyl transferase (Rabggta), an enzyme that attaches geranylgeranyl groups to Rab proteins. Most Rabggta mRNAs from gm tissues skipped exon 1 and lacked a start codon. Rabggta protein and Rab geranylgeranyl transferase (GGTase) activity were reduced 4-fold in gm platelets. Geranylgeranylation and membrane association of Rab27, a Rab GGTase substrate, were significantly decreased in gm platelets. These findings indicate that geranylgeranylation of Rab GTPases is critical for hemostasis. Rab GGTase inhibition may represent a new treatment for thrombocytosis and clotting disorders.
Detter
J C
JC
Departments of Medicine, Molecular Genetics and Microbiology, Pathology and Laboratory Medicine, and Pediatrics, and Center for Mammalian Genetics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA.
Zhang
Q
Q
Mules
E H
EH
Novak
E K
EK
Mishra
V S
VS
Li
W
W
McMurtrie
E B
EB
Tchernev
V T
VT
Wallace
M R
MR
Seabra
M C
MC
Swank
R T
RT
Kingsmore
S F
SF
D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D002455:Cell Division / Q000235:genetics*; D018244:Chromosomes, Artificial, Yeast; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017368:Protein Prenylation; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; D020691:rab GTP-Binding Proteins