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MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections
Ryan M. McCormack, … , Eckhard R. Podack, Steven M. Holland
Ryan M. McCormack, … , Eckhard R. Podack, Steven M. Holland
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e89635. https://doi.org/10.1172/jci.insight.89635.
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Research Article Genetics Infectious disease

MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections

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Abstract

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.

Authors

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

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Figure 1

Perforin-2 domains and locations of patient mutations.

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Perforin-2 domains and locations of patient mutations.
Colored boxes ind...
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.

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