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 tumours 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.