title: Inherited thrombocytopenia caused by reduced platelet production in mice with the gunmetal pigment gene mutation.
abstract: Hereditary macrothrombocytopenia and prolonged bleeding times are associated with the recessive mouse pigment dilution gene gunmetal (gm). Other platelet abnormalities include a mild storage pool deficiency and abnormal expression of two low-molecular-weight guanosine triphosphate binding proteins. These studies were designed to further elucidate the cause of the macrothrombocytopenia. The life span of gunmetal mouse platelets was not significantly different from normal. However, rates of platelet synthesis, measured by sulfate incorporation, were decreased to 25% of normal values. Bone marrow transplantation of normal marrow cells corrected the thrombocytopenia. Furthermore, direct morphologic analysis of mature mutant marrow megakaryocytes by transmission electron microscopy showed reductions in the normal cytoplasmic demarcation membrane system, areas of abnormal membrane complexes, and an increased incidence of emperipolesis. Mutant platelets were relatively more heterogeneous in size and contained unusual elongated and striated inclusions. Mutant megakaryocyte numbers were increased threefold to fivefold over normal numbers in marrow and spleen. Thus, the efficiency of platelet production from gunmetal megakaryocytes is reduced by an order of magnitude. Mutant marrow had a greater proportion of 32N and a smaller proportion of 8N megakaryocytes. Collectively, the results indicate that the gunmetal gene acts intrinsically in megakaryocytes and that an abnormality in this gene causes significant qualitative and quantitative effects on platelet production.
authors.affiliation: Molecular and Cellular Biology Department, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Novak
authors.forename: M
authors.initials: M
authors.lastname: Reddington
authors.forename: L
authors.initials: L
authors.lastname: Zhen
authors.forename: P E
authors.initials: PE
authors.lastname: Stenberg
authors.forename: C W
authors.initials: CW
authors.lastname: Jackson
authors.forename: M P
authors.initials: MP
authors.lastname: McGarry
authors.forename: R T
authors.initials: RT
authors.lastname: Swank
mesh_terms: D000818:Animals; D001483:Base Sequence; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D048429:Cell Size; D002470:Cell Survival; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D006200:Hair Color / Q000235:genetics; D006410:Hematopoiesis; D007425:Intracellular Membranes / Q000648:ultrastructure; D008297:Male; D008533:Megakaryocytes / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011003:Ploidies; D016133:Polymerase Chain Reaction; D013921:Thrombocytopenia / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D019204:GTP-Binding Proteins