Oral Presentation The 5th Prato Conference on Pore Forming Proteins 2021

Solving the mystery of the p.A91V perforin polymorphism (#32)

Ilia Voskoboinik 1 , Paul Lacaze 2 , Thijs Flinsenberg 1 , Helena Jang 3 , John McNeil 2 , Joseph Trapani 1
  1. Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
  3. Department of Clinical Immunology and Allergy, Royal Northshore Hospital, Sydney, NSW, Australia

Perforin (PRF1) is essential for CTL/NK cell cytotoxicity, and inactivating mutations in PRF1 lead to the life-threatening familial haemophagocytic lymphohistiocytosis (FHL).

Approximately 8% of Caucasians carry the c.272C>T polymorphism, encoding the p.A91V substitution, for which structural instability and compromised cytotoxicity have been demonstrated in vitro.  Bi-allelic p.A91V inheritance has been sporadically reported in late onset (adolescent/adult) FHL while both heterozygous and homozygous inheritance of p.A91V has tentatively been linked with heightened risk of haematological cancers and serious autoimmune diseases. Overall, PRF polymorphism A91V was considered pathogenic, often driving pre-emptive therapy of carriers.

Here, we serially monitored NK cell cytotoxicity in an adult male who is homozygous for p.A91V and developed FHL following EBV infection. Surprisingly, reduced NK cytotoxicity was transient and partial, and returned to normal with clinical recovery.

We then investigated the long-term clinical impact of p.A91V inheritance in a cohort of >13,000 healthy elderly individuals >70 years of age (ASPirin in Reducing Events in the Elderly; ASPREE). We found the number of p.A91V homozygotes to be undiminished, with no apparent increased risk of cancer or serious inflammatory disease.

Our studies indicate that p.A91V is unlikely to be causally associated with serious long-term health sequelae, and poses at most a small risk of premature death or life-threatening disease, even for homozygous carriers and, thus, corrects the previous clinical perception that A91V/A91V individuals are immunodeficient.

  1. Jang, H.S., Flinsenberg, T.W.H., Lacaze, P., Thia, K.Y.T., Noori, T., Fernando, S.L., Kerridge, I., Riaz, M., McNeil, J.J., Blombery, P.A., Trapani, J.A., Voskoboinik, I. (2020) Recovery of natural killer cell cytotoxicity in a p.A91V perforin homozygous patient following severe haemophagocytic lymphohistiocytosis. British Journal of Haematology, 190:458-461.
  2. Voskoboinik, I., Lacaze, P., Jang, H.S., Flinsenberg, T.W.H., Fernando, S.L., Kerridge, I., Riaz, M., Sebra, R., Thia, K.Y.T., Noori, T., Schadt, E.E., McNeil, J.J., and Trapani, J.A. (2020) Prevalence and disease predisposition of p.A91V perforin in an aged Caucasian population. Blood, 135:582-584.