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.

KEYWORDS:

• Hereditary cancer
• perforin
• protein misfolding

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Author contributions

M.S.C. researched the study, collected and analyzed the data, and wrote the manuscript; K.G. performed experiments and contributed to writing of the manuscript; I.H. performed experiments; M.L. supervised research and contributed to writing of the manuscript; N.P. collected clinical data and contributed to writing of the manuscript; M.S. collected clinical data; J.T. supervised research and contributed to writing of the manuscript; I.V. supervised research and contributed to writing of the manuscript.