A Novel Pathogenic Variant in PRF1 Associated with Hemophagocytic Lymphohistiocytosis

Abstract

Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL2) results from mutations in PRF1. We described two unrelated individuals who presented with FHL, in whom severely impaired NK cytotoxicity and decrease perforin expression was observed. DNA sequencing of PRF1 demonstrated that both were not only heterozygous for the p.54R > C/91A > V haplotype but also presented with the novel variant p.47G > V at the perforin protein. Perforin mRNA was found to be increased in a individual with that genotype. A carrier of the novel variant also demonstrated altered perforin mRNA and protein expression. Phylogenetic analysis and multiple alignments with perforin orthologous demonstrated a high level of conservation at Gly47. PolyPhen-2 and PROVEAN predicted p.47G > V to be "probably damaging" and "deleterious", respectively. A thermodynamic analysis showed that this variant was highly stabilizing, decreasing the protein internal energy. The ab initio perforin molecular modeling indicated that Gly47 is buried inside the hydrophobic core of the MACPF domain, which is crucial for the lytic pore formation and protein oligomerization. After the in silico induction of the p.47G > V mutation, Val47 increased the interactions with the surrounding amino acids due to its size and physical properties, avoiding a proper conformational change of the domain. To our knowledge, this is the first description supporting that p.47G > V is a pathogenic variant that in conjunction with p.54R > C/91A > V might result in the clinical phenotype of FHL2.

Comprehensive analysis of immune-related genes associated with the microenvironment of patients with unexplained infertility

“…Sidore et al discovered that PRF1 mutation, PRF1:p.A91V, is helpful to regulate different immune subtypes, especially to enhance the memory cytotoxic T cell compartment: effector-memory CD8 bright , CD8 dim , TCR γδ + , and CD8 dim CD28 − T cell pool (64). Perforin pathway interruption leads to autoimmune disorders, neoplastic disease, transplant rejection, and prolonged inflammation (64)(65)(66)(67)(68). Our study revealed that PRF1 was downregulated in unexplained infertile patients.…”

Effects of a natural nutritional supplement on immune cell infiltration and immune gene expression in exercise-induced injury

“…PRF1 is a potent component of NK cells; PRF1 expression levels are positively correlated with the inflammatory toxic effects of NK cells, and PRF1 targeting regulates (enhances or decreases) the activity and function of NK cells (34)(35)(36)(37). Thus, the high expression of PRF1 after exercise is consistent with the high rate of NK cell infiltration.…”

Epigenetic Modification of PD-1/PD-L1-Mediated Cancer Immunotherapy against Melanoma

“…PRF1 is a membrane-attack-complex/PRF (MACPF) protein family and plays an essential role in the functioning of active cytotoxic T cells and NK cells [110]. DNA methylation in tissue-resident memory cells is associated with their function.…”