Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition

Abstract

Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein, we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumors that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition.

Inhibition of the Cytolytic Protein Perforin Prevents Rejection of Transplanted Bone Marrow Stem Cells in Vivo

“…The ability of perforin to disrupt the target cell membrane is critical for enabling entry of the proapoptotic granzymes into the cytoplasm where they trigger target cell death. Mutations that result in loss of perforin expression or function result in fatal immune dysregulation, while partial loss has been associated with hematological or solid cancers. , Conversely, inappropriate perforin activity has been implicated in a variety of pathologies, including insulin-dependent diabetes, juvenile idiopathic arthritis, postviral myocarditis, and postviral acute liver failure − as well as therapy-induced conditions such as allograft rejection and graft versus host disease. − …”

Primary Immunodeficiency and Cancer Predisposition Revisited: Embedding Two Closely Related Concepts Into an Integrative Conceptual Framework

“…The inability of cytotoxic lymphocytes to fend off and kill virus-infected or transformed cells leads to an often uncontrollable hyperactivation of the immune system in form of hemophagocytic lymphohistiocytosis (HLH) (179–181). This distinctive clinical feature is the common denominator of a related group of perforin-deficient hyperinflammatory disorders, so called “perforinopathies,” that may either be due to rare congenital gene-disrupting mono- or biallelic mutations or, in less severe form, due to functionally impairing hypomorphic alleles (182–186). Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is caused by biallelic mutations of the perforin gene ( PRF1 ) (179).…”

Sustained hyperferritinemia in a child with macrophage activation syndrome secondary to systemic juvenile idiopathic arthritis - perforinopathy: case based review

“…Also, there are some studies stating that having heterozygous A91V variant in the PRF1 gene could predispose individuals to leukemia, lymphoma and melanoma. 7,[20][21][22] In our clinic, we do not normally check any fHLH genes in sJIA patients with or without MAS. We wanted to look for perforin and other fHLH gene mutations for this patient because the patient's course was extremely unusual for a sJIA-MAS patient.…”