Perforin-2 is a highly conserved pore-forming protein encoded by macrophage expressed gene 1 (MPEG1). A number of studies have shown that Perforin-2–deficient mice are unable to survive following a bacterial challenge that is nonlethal in WT mice. There is also recent evidence that Mpeg1+/– heterozygous mice display an intermediate killing ability compared with Mpeg1 WT and Mpeg1–/– mice. Despite these in vivo findings, to date, no perforin-2 deficiencies have been associated with human disease. Here, we report four patients with persistent nontuberculous mycobacterial infection who had heterozygous MPEG1 mutations. In vitro, neutrophils, macrophages, and B cells from these patients were unable to kill Mycobacterium avium as efficiently as normal controls. CRISPR mutagenesis validated the deleterious antibacterial activity of these mutations. These data suggest that perforin-2 haploinsufficiency may contribute to human susceptibility to infections with intracellular bacteria.
Ryan M. McCormack, Eva P. Szymanski, Amy P. Hsu, Elena Perez, Kenneth N. Olivier, Eva Fisher, E. Brook Goodhew, Eckhard R. Podack, Steven M. Holland
Colored boxes indicate known domains of the perforin-2 protein. Amino acid ranges for each domain are as follows: signal peptide (SP) from 1–19; membrane-attack-complex-perforin (MACPF) from 30–345; perforin-2 (P2) from 351–653; transmembrane (TM) from 654–674; and cytoplasmic from 675–713. Patient mutations are indicated with arrows.