Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/12686
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dc.contributor.authorHouse, Imran Gen
dc.contributor.authorThia, Kevinen
dc.contributor.authorBrennan, Amelia Jen
dc.contributor.authorTothill, Richarden
dc.contributor.authorDobrovic, Alexanderen
dc.contributor.authorYeh, Wei Zen
dc.contributor.authorSaffery, Richarden
dc.contributor.authorChatterton, Zacen
dc.contributor.authorTrapani, Joseph Aen
dc.contributor.authorVoskoboinik, Iliaen
dc.date.accessioned2015-05-16T02:24:52Z
dc.date.available2015-05-16T02:24:52Z
dc.date.issued2015-03-17en
dc.identifier.citationImmunology and Cell Biology 2015; 93(6): 575-80en
dc.identifier.govdoc25776844en
dc.identifier.otherPUBMEDen
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/12686en
dc.description.abstractThe production and delivery of functional perforin (PRF; PRF1 gene) by cytotoxic lymphocytes maintains immune homeostasis and tumour immune surveillance. In humans, inheritance of the common PRF1 polymorphism, p.A91V, (c.272C>T) found in 8-9% of the Caucasian population, with another mutated allele resulting in reduced PRF function or trafficking, has been shown to result in hyperinflammatory diseases and/or haematological cancers. In this study, we sought to investigate the function of p.A91V on a wild-type (WT) perforin background. We first developed an assay that distinguishes the relative levels of transcription of individual PRF1 alleles, including p.A91V. The p.A91V allele was seen to be expressed at similar levels as the WT allele in primary human natural killer (NK) cells, ruling out that allelic expression imbalance influenced their function. We then demonstrated that the p.A91V mutation results in protein misfolding and an appreciable reduction in NK-cell cytotoxicity in healthy carriers of p.A91V. We propose that this level of cytotoxic dysfunction may readily account for the predisposition to immune-mediated disease in individuals homozygous for p.A91V. Also, the fact that monoallelic mutations of PRF1 decrease NK-cell cytotoxicity should be considered in individuals presenting with the manifestations of immune deficiency states that impinge on NK-cell cytotoxicity.Immunology and Cell Biology advance online publication, 17 March 2015; doi:10.1038/icb.2015.1.en
dc.language.isoenen
dc.titleHeterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals.en
dc.typeJournal Articleen
dc.identifier.journaltitleImmunology and cell biologyen
dc.identifier.affiliationCancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australiaen
dc.identifier.affiliationMurdoch Children's Research Institute; Department of Paediatrics; The University of Melbourne; Royal Children's Hospital, Melbourne, Victoria, Australiaen
dc.identifier.affiliationLudwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg (Melbourne), Victoria, Australiaen
dc.identifier.affiliationDepartment of Immunology and Microbiology, Parkville, Victoria, Australiaen
dc.identifier.affiliationSir Peter MacCallum Department of Oncology, Parkville, Victoria, Australiaen
dc.identifier.affiliationCancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australiaen
dc.identifier.affiliationDepartment of Genetics, University of Melbourne, Parkville, Victoria, Australiaen
dc.identifier.affiliationDepartment of Pathology, University of Melbourne, Parkville, Victoria, Australiaen
dc.identifier.doi10.1038/icb.2015.1en
dc.relation.urlhttps://pubmed.ncbi.nlm.nih.gov/25776844en
dc.type.austinJournal Articleen
local.name.researcherDobrovic, Alexander
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.languageiso639-1en-
item.openairetypeJournal Article-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
crisitem.author.deptSurgery (University of Melbourne)-
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