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
    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.
  • Rashi Gautam
    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.
  • Madonna Reddington
    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.
  • Lucy M. Collinson
    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.
  • Neal G. Copeland
    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.
  • Nancy A. Jenkins
    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.
  • Michael P. McGarry
    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.
  • 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.

抄録

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

収録刊行物

  • Blood

    Blood 100 (1), 128-135, 2002-07-01

    American Society of Hematology

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