A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• Primary immunodeficiencies often result from monogenic disorders, increasing susceptibility to infections.
• Interferon (IFN) pathways are crucial for host defense against various pathogens.

Purpose of the Study:

• To identify genetic defects in a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia.
• To investigate the functional consequences of identified mutations on IFN signaling pathways.

Main Methods:

• Whole-exome sequencing was performed on the patient's DNA.
• Functional assays using patient-derived fibroblasts were conducted to assess IFN-α and IFN-γ signaling.
• Analysis of STAT1/STAT2 phosphorylation, nuclear translocation, and gene expression.

Main Results:

• A homozygous frameshift deletion in IFNGR2 was identified, abolishing IFN-γ signaling.
• A novel homozygous deletion in IFNAR1 (IFNAR1*557Gluext*46) was found, impairing IFN-α signaling and CMV immunity.
• Patient fibroblasts showed impaired IFN-α-induced STAT1/STAT2 phosphorylation and reduced expression of IFN-α-stimulated genes.

Conclusions:

• This study describes a unique digenic immunodeficiency affecting both type I (IFN-α) and type II (IFN-γ) interferon pathways.
• The identified IFNAR1 mutation represents a novel cause of immunodeficiency and highlights the critical role of IFN-α in controlling CMV infections.
• Understanding these distinct IFN pathway defects provides insights into host-pathogen interactions and potential therapeutic strategies.