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Blood, 1 July 2002, Vol. 100, No. 1, pp. 128-135
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The regulation of platelet-dense granules by Rab27a in the ashen
mouse, a model of Hermansky-Pudlak and Griscelli syndromes, is
granule-specific and dependent on genetic background
Edward K. Novak,
Rashi Gautam,
Madonna Reddington,
Lucy M. Collinson,
Neal G. Copeland,
Nancy A. Jenkins,
Michael P. McGarry, and
Richard T. Swank
From the Department of Molecular and Cellular Biology,
Roswell Park Cancer Institute, Buffalo, NY; the Imperial College of
Science, Technology and Medicine, London, United Kingdom; the Mouse
Cancer Genetics Program, National Cancer Institute, Frederick, MD; and
the Department of Biochemistry and Molecular Biology, S.C. Johnson
Research Building, Mayo Clinic, Scottsdale, AZ.
The ashen (ash) mouse, a model for Hermansky-Pudlak
syndrome (HPS) and for a subset of patients with Griscelli syndrome,
presents with hypopigmentation, prolonged bleeding times, and platelet storage pool deficiency due to a mutation which abrogates expression of
the Rab27a protein. Platelets of mice with the ashen mutation on
the C3H/HeSnJ inbred strain background have greatly reduced amounts of dense granule components such as serotonin and adenine nucleotides though near-normal numbers of dense granules as enumerated by the dense granule-specific fluorescent dye mepacrine. Thus, essentially normal numbers of platelet dense granules are produced but
the granule interiors are abnormal. Collagen-mediated aggregation of
mutant platelets is significantly depressed. No abnormalities in the
concentrations or secretory rates of 2 other major platelet granules,
lysosomes and alpha granules, were apparent. Similarly, no platelet
ultrastructural alterations other than those involving dense granules
were detected. Therefore, Rab27a regulates the synthesis and secretion
of only one major platelet organelle, the dense granule. There were
likewise no mutant effects on levels or secretion of lysosomal enzymes
of several other tissues. Together with other recent analyses of the
ashen mouse, these results suggest a close relationship between
platelet dense granules, melanosomes of melanocytes and secretory
lysosomes of cytotoxic T lymphocytes, all mediated by Rab27a.
Surprisingly, the effects of the ashen mutation on platelet-dense
granule components, platelet aggregation, and bleeding times were
highly dependent on genetic background. This suggests that bleeding
tendencies may likewise vary among patients with Griscelli syndrome and
HPS with Rab27a mutations.
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