title: Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.
abstract: Mutations decreasing function of the Fas death receptor cause the autoimmune lymphoproliferative syndrome (ALPS) with autoimmune manifestations, spleen/lymph node enlargement, and expansion of CD4/CD8-negative T cells. Dianzani Autoimmune Lymphoproliferative Disease (DALD) is a variant lacking this expansion. Perforin is involved in cell-mediated cytotoxicity and its biallelic mutations cause familial hemophagocytic lymphohistiocytosis (HLH). We previously described an ALPS patient carrying heterozygous mutations of the Fas and perforin genes and suggested that they concurred in ALPS. This work extends the analysis to 14 ALPS, 28 DALD, and 816 controls, and detects an N252S amino acid substitution in 2 ALPS, and an A91V amino acid substitution in 6 DALD. N252S conferred an OR = 62.7 (P = .0016) for ALPS and A91V conferred an OR = 3 (P = .016) for DALD. Copresence of A91V and variations of the osteopontin gene previously associated with DALD conferred an OR = 17 (P = .0007) for DALD. In one N252S patient, NK activity was strikingly defective in early childhood, but became normal in late childhood. A91V patients displayed lower NK activity than controls. These data suggest that perforin variations are a susceptibility factor for ALPS/DALD development in subjects with defective Fas function and may influence disease expression.
authors.affiliation: Pediatric Haematology-Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, University of Pavia, Pavia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Clementi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cappellano
authors.forename: Elisa
authors.initials: E
authors.lastname: Cerutti
authors.forename: Massimo
authors.initials: M
authors.lastname: Ferretti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orilieri
authors.forename: Irma
authors.initials: I
authors.lastname: Dianzani
authors.forename: Marina
authors.initials: M
authors.lastname: Ferrarini
authors.forename: Marco
authors.initials: M
authors.lastname: Bregni
authors.forename: Cesare
authors.initials: C
authors.lastname: Danesino
authors.forename: Valeria
authors.initials: V
authors.lastname: Bozzi
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: Putti
authors.forename: Franco
authors.initials: F
authors.lastname: Cerutti
authors.forename: Angela
authors.initials: A
authors.lastname: Cometa
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Rita
authors.initials: R
authors.lastname: Maccario
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
mesh_terms: D019943:Amino Acid Substitution; D001327:Autoimmune Diseases / Q000235:genetics*; D003602:Cytotoxicity, Immunologic; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D018655:Lymphocyte Count; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics*; D019014:fas Receptor / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin