title: Perforin gene mutations in patients with acquired aplastic anemia.
abstract: Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural killer cells. Inherited perforin mutations account for 20% to 40% of familial hemophagocytic lymphohistiocytosis, a fatal disease of early childhood characterized by the absence of functional perforin. Aplastic anemia, the paradigm of immune-mediated bone marrow failure syndromes, is characterized by hematopoietic stem cell destruction by activated T cells and Th1 cytokines. We examined whether mutations in the perforin gene occurred in acquired aplastic anemia. Three nonsynonymous PRF1 mutations among 5 unrelated patients were observed. Four of 5 patients with the mutations showed some hemophagocytosis in the bone marrow at diagnosis. Perforin protein levels in these patients were very low or absent, and perforin granules were completely absent. Natural killer (NK) cell cytotoxicity from these patients was significantly decreased. Our data suggest that PRF1 genetic alterations help explain the aberrant proliferation and activation of cytotoxic T cells and may represent genetic risk factors for bone marrow failure.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA. solomoue@nhlbi.nih.gov
authors.forename: Elena E
authors.initials: EE
authors.lastname: Solomou
authors.forename: Federica
authors.initials: F
authors.lastname: Gibellini
authors.forename: Brian
authors.initials: B
authors.lastname: Stewart
authors.forename: Daniela
authors.initials: D
authors.lastname: Malide
authors.forename: Maria
authors.initials: M
authors.lastname: Berg
authors.forename: Valeria
authors.initials: V
authors.lastname: Visconte
authors.forename: Spencer
authors.initials: S
authors.lastname: Green
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000741:Anemia, Aplastic / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D001853:Bone Marrow; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D054353:Perforin; D010587:Phagocytosis; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics* / Q000276:immunology
chemical_list: D008562:Membrane Glycoproteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin