PRF1 – Hereditary Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is an autosomal recessive hyperinflammatory syndrome caused by germline biallelic mutations in PRF1, the gene encoding the pore-forming protein perforin. Affected infants and children present with fever, cytopenias, hepatosplenomegaly and coagulopathy due to uncontrolled activation of T lymphocytes and macrophages. Without prompt recognition and hematopoietic stem cell transplantation, FHL2 is rapidly fatal, underscoring the critical role of perforin in lymphocyte cytotoxicity.

Genetic studies have identified over 200 probands from more than 75 unrelated families harboring PRF1 mutations, including missense, nonsense, frameshift and small indels, confirming autosomal recessive inheritance and robust segregation of biallelic variants with disease (PMID:11179007, PMID:15632205). A recurrent founder variant, c.666C>A (p.His222Gln), has been reported in multiple populations and presents both in homozygous and compound-heterozygous states (PMID:15205266).

The PRF1 variant spectrum comprises >30 unique missense changes, >20 truncating alleles and several in-frame deletions across the membrane attack complex/perforin domain and C2 calcium-binding domain. Functional assessment of mutant perforin proteins in patient NK/CTLs and heterologous expression systems shows impaired or absent perforin processing, calcium-dependent lipid binding, and cytolytic activity, consistent with loss-of-function (PMID:12060139).

Segregation analyses document ≥19 additional affected relatives demonstrating co-segregation of PRF1 variants with FHL2 phenotype in multiplex families, fulfilling Mendelian expectations for autosomal recessive inheritance and reinforcing the causal relationship (PMID:15632205).

Mechanistically, PRF1 mutations disrupt cytotoxic granule exocytosis or perforin pore formation, leading to defective clearance of activated lymphocytes and marked cytokine release. Animal knockout and cellular models recapitulate the human phenotype, and rescue experiments confirm that restoration of perforin function corrects cytotoxic deficits.

No credible conflicting evidence has been reported. The breadth of genetic and functional data accumulated over two decades establishes a Definitive gene–disease relationship between PRF1 and hereditary hemophagocytic lymphohistiocytosis. Key take-home: PRF1 biallelic loss-of-function variants underlie FHL2, and genetic testing for PRF1 is essential for early diagnosis, prognostic counseling, and selection of curative stem cell transplantation.

References

• American Journal of Human Genetics • 2001 • Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis PMID:11179007
• British Journal of Haematology • 2002 • Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis PMID:12060139
• Blood • 2005 • Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions PMID:15632205
• Blood • 2004 • Unusual immunophenotype of CD8+ T cells in familial hemophagocytic lymphohistiocytosis PMID:15205266

Evidence Based Scoring (AI generated)