Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function

Voskoboinik, Ilia; Sutton, Vivien R.; Ciccone, Annette; House, Colin M.; Chia, Jenny; Darcy, Phillip K.; Yagita, Hideo; Trapani, Joseph A.

doi:10.1182/blood-2007-02-072850

Cited by 83 publications

(88 citation statements)

References 28 publications

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“…16,17 Risma et al 18 classified A91V as a class 1 missense mutation with limited functional impact that allows partial maturation of the protein. Voskoboinik et al 19 have recently used a complementation assay with perforin-knockout primary CTL to show that A91V reduces both the steady-state level of perforin expression in effector cells ('presynaptic' dysfunction) and its intrinsic lytic capacity on target cells, and also displays some dominant-negative effect on the wild-type protein ('postsynaptic' dysfunction).…”

Section: Discussionmentioning

confidence: 99%

Variations of the perforin gene in patients with multiple sclerosis

et al. 2008

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Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P ¼ 0.0166; odds ratio (OR) ¼ 2.06, 95% confidence interval (CI): 1.13-3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P ¼ 0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P ¼ 0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR ¼ 1.38 (95% CI ¼ 1.10-1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.

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Section: Discussionmentioning

confidence: 99%

Variations of the perforin gene in patients with multiple sclerosis

et al. 2008

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“…We have already extensively tested and validated this methodology to demonstrate that the common PRF variant hA91V results in a partial loss of PRF cytotoxicity (19), and therefore some of the functional assays with this allele have not been reported again in the current study. The A91V allele has been found in up to 9% of individuals in several population surveys.…”

Section: Resultsmentioning

confidence: 99%

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

Chia

Yeo

Whisstock

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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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 perforinmediated cytotoxicity and cancer susceptibility in humans and establishes the paradigm that temperature sensitivity of perforin function is a predictor of FHL severity.hemophagocytic lymphohistiocytosis ͉ immunodeficiency ͉ leukemia ͉ lymphoma

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“…The A91V mutation affects PRF folding and stability within the effector cell, and as a result greatly reduces its intrinsic cytolytic activity. [79][80][81] However, within the environment of PRF-deficient CTLs, the mutant recovered 30-50% of the wild-type PRF activity. 80 Interestingly, in vitro A91V also displayed a mild dominant-negative effect.…”

Section: A91v Polymorphism Of Perforinmentioning

confidence: 99%

“…[79][80][81] However, within the environment of PRF-deficient CTLs, the mutant recovered 30-50% of the wild-type PRF activity. 80 Interestingly, in vitro A91V also displayed a mild dominant-negative effect. 80 This phenomenon is potentially very important, as unlike most other naturally occurring PRF mutants that are almost completely degraded in the effector cell and cannot inhibit wild-type PRF function, the steady-state level of A91V expression is significant.…”

Section: A91v Polymorphism Of Perforinmentioning

confidence: 99%

“…80 Interestingly, in vitro A91V also displayed a mild dominant-negative effect. 80 This phenomenon is potentially very important, as unlike most other naturally occurring PRF mutants that are almost completely degraded in the effector cell and cannot inhibit wild-type PRF function, the steady-state level of A91V expression is significant. Taken together, the combination of functional and clinical observations suggests that when co-inherited with the normal allele, A91V is unlikely to have a pathological role.…”

Section: A91v Polymorphism Of Perforinmentioning

confidence: 99%

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Perforin deficiency and susceptibility to cancer

et al. 2010

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Cytotoxic lymphocytes (CLs) are the killer cells that destroy intracellular pathogen-infected and transformed cells, predominantly through the cytotoxic granule-mediated death pathway. Soluble cytotoxic granule components, including pore-forming perforin and pro-apoptotic serine proteases, granzymes, synergize to induce unscheduled apoptosis of the target cell. A complete loss of CL function results in an aggressive immunoregulatory disorder, familial hemophagocytic lymphohistiocytosis, whereas a partial loss of function seems to be a factor strongly predisposing to hematological malignancies. This review discusses the pathological manifestations of CL deficiencies due to impaired perforin function and describes novel aspects of perforin biology. Cell Death and Differentiation (2010) 17, 607-615; doi:10.1038/cdd.2009; published online 15 January 2010Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, collectively called cytotoxic lymphocytes (CLs), kill virusinfected and transformed cells through a number of contactdependent mechanisms. 1,2 Engagement of death receptors by membrane-bound members of the TNF superfamily of death ligands is critical for maintaining lymphoid homeostasis in the host. By contrast, studies of gene deficiencies indicate that defects of the granule exocytosis pathway result in a failure to eliminate infected cells or those that pose a risk of subsequent malignancy. Although cytotoxic granules contain diverse toxins that together contribute to apoptosis induction, this review will deal exclusively with the critical role of the pore-forming protein perforin (PRF) as an essential enabler of target-cell apoptosis, and its more recently described role as a potential 'extrinsic' tumor suppressor.Perforin is a 67-kDa pore-forming protein that is stored and released from the secretory granules (SGs) of CLs along with a number of pro-apoptotic serine protease granzymes that display broad substrate specificities. 3 Following exocytic release, PRF and the granzymes are exposed to the neutral pH and calciumrich environment of the immune synapse. 4 After binding calcium through their C2 domains, PRF monomers acquire the ability to bind generic lipids in the target cell membrane, 5 and then coalesce into large transmembrane pores that permit the granzymes to access key death substrates in the cytosol. [6][7][8] Although the diverse apoptotic pathways triggered by granzymes have been extensively studied and are now understood in considerable detail, it is only of late that insights into the molecular and cellular functions of PRF have been even partly addressed.In this review, we will re-examine the pathological consequences of PRF deficiency, both in mice and humans. In doing so, important differences in PRF biology between these species will be described. We will discuss the pathogenic effect of a number of recently described missense mutations of human PRF. In particular, although the complete absence of PRF function typically results in an aggressive, fatal immunoregulatory disorder of ea...

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Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function

Cited by 83 publications

References 28 publications

Variations of the perforin gene in patients with multiple sclerosis

Variations of the perforin gene in patients with multiple sclerosis

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

Perforin deficiency and susceptibility to cancer

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