title: 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.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Novak
authors.forename: Rashi
authors.initials: R
authors.lastname: Gautam
authors.forename: Madonna
authors.initials: M
authors.lastname: Reddington
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Collinson
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Michael P
authors.initials: MP
authors.lastname: McGarry
authors.forename: Richard T
authors.initials: RT
authors.lastname: Swank
mesh_terms: D000244:Adenosine Diphosphate / Q000172:deficiency; D000255:Adenosine Triphosphate / Q000172:deficiency; D000818:Animals; D001792:Blood Platelets / Q000737:chemistry / Q000648:ultrastructure*; D003594:Cytoplasmic Granules / Q000737:chemistry / Q000187:drug effects*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006470:Hemorrhage / Q000209:etiology / Q000235:genetics; D022861:Hermanski-Pudlak Syndrome / Q000150:complications / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D010981:Platelet Storage Pool Deficiency / Q000235:genetics; D012701:Serotonin / Q000172:deficiency; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D000075745:rab27 GTP-Binding Proteins; D012701:Serotonin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins