[No authors listed]
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.
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Ang, Ctsg, Gzmb, Gzmc, Gzmd, Gzme, Gzmf, Ltb4r1, Mcpt1, Mcpt2, Mcpt4, Cma1, Mcpt9, Mcptl, Myh6, Nedd8, Tcra, Rabggta, D14Mit61, D14Mit62, D14Mit63, D14Mit64, D14Mit65, D14Mit66, D14Mit83, D14Mit259, D14Mit261, D14Mit101, D14Mit121, D14Mit142, D14Mit153, D14Mit154, D14Mit155, D14Mit156, D14Mit215, Pck2
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