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

Mohammed S. Chaudhry, Kimberly C. Gilmour, Imran G. House, Mark Layton, Nicki Panoskaltsis, Mamta Sohal, Joseph A. Trapani, Ilia Voskoboinik

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Article numbere1179415
JournalOncoImmunology
Volume5
Issue number7
DOIs
StatePublished - 2 Jul 2016
Externally publishedYes

Keywords

  • Hereditary cancer
  • perforin
  • protein misfolding

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