Journal article
Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer
J Chia, PY Kim, JC Whisstock, MA Dunstone, JA Trapani, I Voskoboinik
Proceedings of the National Academy of Sciences of the United States of America | Published : 2009
Abstract
The pore-forming protein perforin is critical for defense against many human pathogens and for preventing a catastrophic collapse of immune homeostasis, manifested in infancy as Type 2 familial hemophagocytic lymphohistiocytosis (FHL). However, no evidence has yet linked defective perforin cytotoxicity with cancer susceptibility in humans. Here, we examined perforin function in every patient reported in the literature who lived to at least 10 years of age without developing FHL despite inheriting mutations in both of their perforin (PRF1) alleles. Our analysis showed that almost 50% of these patients developed at least 1 hematological malignancy in childhood or adolescence. The broad range o..
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Funding Acknowledgements
We thank J. Cebon, D. Bowtell, J. Sambrook, M. Smyth, G. McArthur, and J. Zalcberg for helpful comments on the manuscript. This work was supported by a Senior Principal Research Fellowship and Program Grant (to J. A. T.), a R. D. Wright Fellowship and Project Grant (to I. V.), a Doherty Fellowship (to M. D.)(all from the National Health and Medical Research Council of Australia), and an Australian Research Council Federation Fellowship (to J. C. W.).