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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.
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IMMUNOBIOLOGY
A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin
Christina Trambas,
Federico Gallo,
Daniela Pende,
Stefania Marcenaro,
Lorenzo Moretta,
Carmela De Fusco,
Alessandra Santoro,
Luigi Notarangelo,
Maurizio Arico, and
Gillian M. Griffiths
From the Sir William Dunn School of Pathology, Oxford, United Kingdom; the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; the Istituto G. Gaslini, Genova, Italy; the Dipartimento di Medicina Sperimentale (DIMES) and Centro di Eccellenza per la Ricerca Biomedica, University of Genova, Genova, Italy; Onco Ematologia Pediatrica Ospedale Pausilipon, Napoli, Italy; the Department of Pediatrics and "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, Brescia, Italy; and Onco Ematologia Pediatrica, Ospedale dei Bambini "G. Di Cristina," Palermo, Italy.
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 (CTLs) and natural killer (NK) cells to lyse target cells is greatly reduced. Here we demonstrate that perforin from this patient is not recognized 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 recognized 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 CTLs from the patient. Patient CTLs 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 CTLs and NK cells from this patient and are likely to contribute to the pathogenesis of HLH.
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