Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer

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 cytotoxic...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2009-06, Vol.106 (24), p.9809-9814
Main Authors:	Chia, Jenny, Yeo, Kim Pin, Whisstock, James C, Dunstone, Michelle A, Trapani, Joseph A, Voskoboinik, Ilia
Format:	Article
Language:	eng
Subjects:	Adolescence Age Alleles Biological Sciences Blood Cancer Children Cytotoxicity Genetic mutation Genetic Predisposition to Disease Hemophagocytic lymphohistiocytosis Heredity Histiocytosis Homeostasis Humans Lymphocytosis Lymphohistiocytosis, Hemophagocytic - immunology Lymphoma Malignancy Missense mutation Mutation Mutation, Missense Natural killer cells Pathogens Perforin Perforin - chemistry Perforin - genetics Perforin - physiology pore-forming proteins Protein Folding Proteins Surveillance T lymphocytes Temperature Temperature effects Toxicity
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Summary:	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 of pathologies argued strongly against a common environmental or viral cause for the extraordinary cancer incidence. Functionally, what distinguished these patients was their inheritance of PRF1 alleles encoding temperature-sensitive missense mutations. By contrast, truly null missense mutations with no rescue at the permissive temperature were associated with the more common severe presentation with FHL in early infancy. Our study provides the first mechanistic evidence for a link between defective perforin-mediated cytotoxicity and cancer susceptibility in humans and establishes the paradigm that temperature sensitivity of perforin function is a predictor of FHL severity.
ISSN:	0027-8424 1091-6490