Mendelian susceptibility to mycobacterial infection in man

Selective susceptibility to weakly pathogenic mycobacteria, such as bacillus Calmette-Guérin (BCG) vaccine and environmental non-tuberculous mycobacteria (NTM), has long been suspected to be a Mendelian disorder but its molecular basis remained elusive. Recently, mutations in the interferon-gamma receptor ligand-binding chain (IFN gamma R1), interferon-gamma receptor signaling chain (IFN gamma R2), Signal Transducer and Activator of Transcription-1 (STAT-1), interleukin-12 p40 subunit (IL-12 p40), and interleukin-12 receptor beta 1 chain (IL-12R beta 1) genes have been identified in a number of patients with severe BCG or NTM infection. Dominant or recessive alleles causing complete or partial cellular defects have been found to define nine different inheritable disorders. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon gamma-mediated immunity in the control of mycobacteria in man. The genetic and immunologic heterogeneity of this syndrome makes accurate diagnosis challenging but vital as decisions about the most appropriate treatment are best taken based on an accurate molecular diagnosis.