ArticleImmunology and cell biology2015
Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals.
Article in Immunology and cell biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- Is a variant of uncertain significance always 'insignificant'? A systematic review on PRF1 A91V in Hemophagocytic Lymphohistocytosis and comparative analysis with Still's disease.Orphanet journal of rare diseases · 2026Pooled it
- Germline Variants in the Immune Response-Related Genes: Possible Modifying Effect on Age-DependentCancers · 2025Article
- Severe Aplastic Anemia Complicated with Fatal Invasive Fungal Infections in a Young Patient Harboring Perforin Gene Polymorphisms.Hematology reports · 2025Article
- Perforin 1 in Cancer: Mechanisms, Therapy, and Outlook.Biomolecules · 2024Review
- Late Onset of Primary Hemophagocytic Lymphohistiocytosis (HLH) with a Novel Constellation of Compound Heterozygosity Involving Two Missense Variants in theInternational journal of molecular sciences · 2024Review
- Hemophagocytic lymphohistiocytosis and clonally related T-cell malignancies in a pediatric patient.Pediatric blood & cancer · 2023Article
- The Multifaceted Immunology of Cytokine Storm Syndrome.Journal of immunology (Baltimore, Md. : 1950) · 2023Review
- Rare genetic variants involved in multisystem inflammatory syndrome in children: a multicenter Brazilian cohort study.Frontiers in cellular and infection microbiology · 2023Article
- Immune Response Gaps Linked to SARS-CoV-2 Infection: Cellular Exhaustion, Senescence, or Both?International journal of molecular sciences · 2022Article
- Article
- [Prognostic and monitoring biomarkers in chronic inflammatory demyelinating polyneuropathy].Revista de neurologia · 2022Review
- Natural Killer Cells in Multiple Sclerosis: Entering the Stage.Frontiers in immunology · 2022Review
- A rapid turnaround gene panel for severe autoinflammation: Genetic results within 48 hours.Frontiers in immunology · 2022Article
- Perforin, COVID-19 and a possible pathogenic auto-inflammatory feedback loop.Scandinavian journal of immunology · 2021Review
- Molecular Genetics Diversity of Primary Hemophagocytic Lymphohistiocytosis among Polish Pediatric Patients.Archivum immunologiae et therapiae experimentalis · 2021Article
- MAIT cells regulate NK cell-mediated tumor immunity.Nature communications · 2021Article
- Genetic biomarkers for intravenous immunoglobulin response in chronic inflammatory demyelinating polyradiculoneuropathy.European journal of neurology · 2021Article
- Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis.Frontiers in immunology · 2021Review
- Unusual Prominent Pulmonary Involvement in a Homozygous PRF1 Gene Variant in a Female Patient.Journal of clinical immunology · 2021Article
- Highways to hell: Mechanism-based management of cytokine storm syndromes.The Journal of allergy and clinical immunology · 2020Review
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The 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.
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