title: Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis.
abstract: 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.
authors.affiliation: 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.
authors.forename: J C
authors.initials: JC
authors.lastname: Detter
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.forename: E H
authors.initials: EH
authors.lastname: Mules
authors.forename: E K
authors.initials: EK
authors.lastname: Novak
authors.forename: V S
authors.initials: VS
authors.lastname: Mishra
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: E B
authors.initials: EB
authors.lastname: McMurtrie
authors.forename: V T
authors.initials: VT
authors.lastname: Tchernev
authors.forename: M R
authors.initials: MR
authors.lastname: Wallace
authors.forename: M C
authors.initials: MC
authors.lastname: Seabra
authors.forename: R T
authors.initials: RT
authors.lastname: Swank
authors.forename: S F
authors.initials: SF
authors.lastname: Kingsmore
mesh_terms: 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*
chemical_list: D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; D020691:rab GTP-Binding Proteins