Jc. Detter et al., Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis, P NAS US, 97(8), 2000, pp. 4144-4149
Citations number
29
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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 delt
a-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-s
ubunit 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 geranylger
anyl transferase (GGTase) activity were reduced 4-fold in gm platelets. Ger
anylgeranylation 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 di
sorders.