Perforin, encoded by PRF1, is a pore-forming protein that polymerizes and forms a channel in the target cell membrane. In the presence of calcium, it penetrates the membrane of the target cell, where it polymerizes to form a cell death–inducing pore. Mutations in the gene encoding perforin, PRF1, were first associated with the hyperinflammatory syndrome hemophagocytic lymphohistiocytosis (HLH) in 1999 (PMID: 10583959). Since the first report, more than 100 different mutations in PRF1 have been described (PMIDs: 14757862, 17873118, 26342526, 32542393, 33746956).
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation. Clinical and laboratory signs of HLH reflect intense inflammation, caused by defective eradication of infected target cells and inability to maintain immune homeostasis through killing of activated immune cells (PMID: 26184781). HLH is classified as familial (FHL) when associated with biallelic mutation in one of a set of functionally related genes or with familial recurrence (PMID: 33746956).
We scored six PRF1 variants (nonsense, frameshift, and missense) that have been reported in multiple publications (PMIDs: 10583959, 11179007, 14757862, 15365097, 15741215, 16860143, 26342526 32542393). Mechanism of pathogenicity seems to be biallelic loss of function. Both homozygous and compound heterozygous patients were reported. Patients with a monoallelic mutation, and a partial degranulation defect were also reported but not scored in this curation (PMID: 26342526).
Experimental evidence also supports this gene-disease relationship. Single cell expression analysis revealed that perforin is selectively expressed in cytotoxic T lymphocytes and NK cells. Little or no perforin in the granules of the patients studied compared to control cells was detected by immunostaining (PMID: 10583959). Whereas RBL cells that showed wild-type perforin (67 kD) expression, efficiently killed Jurkat target cells to which they were conjugated, prf1 mutant cells showed expression of a truncated ( approximately 45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules (PMID: 15365097).
In summary, there is definitive evidence supporting a gene-disease relationship between variants in PRF1 and Familial Hemophagocytic Lymphohistiocytosis 2. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Primary Immune Regulatory Disorders GCEP on August 15, 2023 (SOP Version 9).
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