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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3079-3084. Prepublished online as a Blood First Edition Paper on May 23, 2006; DOI 10.1182/blood-2006-02-001412. This Article Full Text (PDF) All Versions of this Article: blood-2006-02-001412v1 108/9/3079    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Clementi, R. Articles by Dianzani, U. Search for Related Content PubMed PubMed Citation Articles by Clementi, R. Articles by Dianzani, U. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 3, 2006 Accepted May 9, 2006 Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective fas function Rita Clementi, Annalisa Chiocchetti, Giuseppe Cappellano, Elisa Cerutti, Massimo Ferretti, Elisabetta Orilieri, Irma Dianzani, Marina Ferrarini, Marco Bregni, Cesare Danesino, Valeria Bozzi, Maria Caterina Putti, Franco Cerutti, Angela Cometa, Franco Locatelli, Rita Maccario, Ugo Ramenghi, and Umberto Dianzani* Pediatric Haematology-Oncology, IRCCS Policlinico San Matteo, Pavia, Italy Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Medical Sciences Laboratory of Tumor Immunology and Department of Oncology, Scientific Institute H. S. Raffaele, Mila Division of Hematology-Bone Marrow Transplantation, Scientific Institute H. S. Raffaele, Milano, Ita Department of Biology and Medical Genetics, University of Pavia and IRCCS Policlinico San Matteo, Pa Pediatric Haematology-Oncology, Department of Pediatrics, University of Padua, Padova, Italy Department of Pediatrics, University of Turin, Turin, Italy * Corresponding author; email: dianzani{at}med.unipmn.it. 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 a N252S amino acid substitution in 2 ALPS, and an A91V amino acid substitution in 6 DALD. N252S conferred an OR=62.7 (P=0.0016) for ALPS and A91V conferred an OR=3 (P=0.016) for DALD. Co-presence of A91V and variations of the osteopontin gene previously associated with DALD conferred an OR=17 (P=0.0007) for DALD. In one N252S patient, NK activity was strikingly defective in early childhood, but became normal in the 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Orilieri, G. Cappellano, R. Clementi, A. Cometa, M. Ferretti, E. Cerutti, F. Cadario, M. Martinetti, D. Larizza, V. Calcaterra, et al. Variations of the Perforin Gene in Patients With Type 1 Diabetes Diabetes, April 1, 2008; 57(4): 1078 - 1083. [Abstract] [Full Text] [PDF] A Trizzino, U z. Stadt, I Ueda, K Risma, G Janka, E Ishii, K Beutel, J Sumegi, S Cannella, D Pende, et al. Genotype phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations J. Med. Genet., January 1, 2008; 45(1): 15 - 21. [Abstract] [Full Text] [PDF] V. Mateo, M. Menager, G. de Saint-Basile, M.-C. Stolzenberg, B. Roquelaure, N. Andre, B. Florkin, F. le Deist, C. Picard, A. Fischer, et al. Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes Blood, December 15, 2007; 110(13): 4285 - 4292. [Abstract] [Full Text] [PDF] I. Voskoboinik, V. R. Sutton, A. Ciccone, C. M. House, J. Chia, P. K. Darcy, H. Yagita, and J. A. Trapani Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function Blood, August 15, 2007; 110(4): 1184 - 1190. [Abstract] [Full Text] [PDF]

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