title: Perforin gene defects in familial hemophagocytic lymphohistiocytosis.
abstract: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22, 10q21-22, or another as yet undefined locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22-linked FHL. Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation.
authors.affiliation: Department of Pathology and the Graduate Program in Immunology, University of Texas Southwestern Medical School, Dallas, TX 75235, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Stepp
authors.forename: R
authors.initials: R
authors.lastname: Dufourcq-Lagelouse
authors.forename: F
authors.initials: F
authors.lastname: Le Deist
authors.forename: S
authors.initials: S
authors.lastname: Bhawan
authors.forename: S
authors.initials: S
authors.lastname: Certain
authors.forename: P A
authors.initials: PA
authors.lastname: Mathew
authors.forename: J I
authors.initials: JI
authors.lastname: Henter
authors.forename: M
authors.initials: M
authors.lastname: Bennett
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: G
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: V
authors.initials: V
authors.lastname: Kumar
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D018388:Codon, Terminator; D003594:Cytoplasmic Granules / Q000737:chemistry; D003602:Cytotoxicity, Immunologic; D016368:Frameshift Mutation; D008040:Genetic Linkage; D053804:Granzymes; D006579:Heterozygote; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D020125:Mutation, Missense; D054353:Perforin; D017354:Point Mutation; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000276:immunology
chemical_list: D018388:Codon, Terminator; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases