Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition marked by predisposition to severe clinical symptoms following infection with weakly virulent mycobacterial strains and other intracellular pathogens. Jean-Laurent Casanova and colleagues now report loss-of-function mutations in ISG15 as a new cause of MSMD (Science, published online 2 August 2012; doi:10.1126/science.1224026). The authors applied exome sequencing and linkage analysis to analyze two unrelated consanguineous families with unexplained MSMD. In both families, they identified loss-of-function mutations in ISG15, which encodes a ubiquitin-like protein previously implicated in antiviral defense through studies in mice. Unlike ISG15-deficient mice, human subjects with homozygous ISG15 mutations did not show enhanced susceptibility to viral infections. Instead, the authors found that blood leukocytes from the affected individuals were deficient in the production of interferon-γ, which likely accounts for the enhanced susceptibility of these individuals to mycobacterial disease. The clinical and immunological phenotypes associated with ISG15 mutations suggest that the secreted form of ISG15 acts as a key inducer of interferon-γ in response to mycobacterial infections but that its contribution to antiviral immunity in humans is largely redundant with other pathways.
This is a preview of subscription content, access via your institution