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Blood, 1 August 2005, Vol. 106, No. 3, pp. 932-937. Prepublished online as a Blood First Edition Paper on March 1, 2005; DOI 10.1182/blood-2004-09-3713. This Article Full Text (PDF) All Versions of this Article: 2004-09-3713v1 106/3/932    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 Trambas, C. Articles by Griffiths, G. M Search for Related Content PubMed PubMed Citation Articles by Trambas, C. Articles by Griffiths, G. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 29, 2004 Accepted January 26, 2005 A single amino acid change, A91V, lead to conformational changes which can impair processing to the active form of perforin Christina Trambas, Federico Gallo, Daniela Pende, Stefania Marcenaro, Lorenzo Moretta, Carmela De Fusco, Luigi Notarangelo, Maurizio Arico, and Gillian M Griffiths* Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy Istituto G. Gaslini, Genova, Italy Istituto G. Gaslini, Genova, Italy; University of Genova, Dipartimento di Medicina Sperimentale (DIMES), Genova, Italy; University of Genova, Centro di Eccellenza per la Ricerca Biomedica, Genova, Italy Onco Ematologia Pediatrica Ospedale Pausilipon, Napoli, Italy Department of Pediatrics and 'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia, Brescia, Italy Onco Ematologia Pediatrica, Ospedale dei Bambini 'G. Di Cristina', Palermo, Italy * Corresponding author; email: gillian.griffiths{at}path.ox.ac.uk. Mutations in the perforin gene have been found in patients with hemophagocytic lymphohistiocytosis (HLH), a rare autosomal recessive disease. We describe a patient expressing perforin with amino acid changes, A91V and W374X. The ability of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to lyse target cells is greatly reduced. Here we demonstrate that perforin from this patient is not recognised using an antibody raised against native perforin (G9), but is readily detected using an antibody raised against a peptide epitope (2d4), suggesting that the epitope recognised by G9 is destroyed by the change at A91V. Immunoblotting reveals no protein corresponding to the truncated transcript encoded by W374X, revealing that only perforin with the A91V change is expressed in CTL from the patient. Patient CTL show bands corresponding to the immature and intermediate forms of perforin, but the mature active form of perforin is absent or barely detectable. The conformational changes and impaired cleavage of A91V perforin are likely to explain the reduced cytotoxicity in CTL and NK cells from this patient and is likely to contribute to the pathogenesis of HLH. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. L. Meade, E. B. Wilson, T. 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