Two patients with complete defects in interferon gamma receptor-dependent signaling

Area of Science:

• Immunology
• Genetics

Background:

• Interferon-gamma (IFN-γ) signaling is crucial for controlling intracellular pathogens, particularly mycobacteria.
• Defects in the IFN-γ receptor 1 (IFNGR1) chain can lead to severe immunodeficiency.
• Understanding these genetic defects is vital for diagnosing and managing unusual infections.

Observation:

• Two patients presented with unusual and severe mycobacterial infections.
• Both patients were diagnosed with homozygous deleterious mutations in the IFNGR1 gene.
• Patient 1 experienced severe complications post-BCG vaccination, while Patient 2 had recurrent atypical mycobacterial infections.

Findings:

• Patient 1 had a C71Y mutation, leading to absent IFNGR1 protein expression and signaling.
• Patient 2 had a splice-site mutation causing a truncated IFNGR1 protein lacking the transmembrane domain.
• Both mutations resulted in undetectable protein expression and complete absence of IFN-γ dependent signaling.

Implications:

• Homozygous IFNGR1 mutations confer a profound susceptibility to mycobacterial infections.
• These findings highlight the critical role of the IFNGR1 pathway in host defense against mycobacteria.
• Genetic screening for IFNGR1 mutations should be considered in patients with unexplained mycobacterial diseases.