In a novel form of IFN - γ receptor 1 deficiency , cell surface receptors fail to bind IFN - γ

Complete IFN-γ receptor ligand-binding chain (IFNγR1) deficiency is a rare, life-threatening, autosomal recessive human immune deficiency (MIM107470) (1, 2). Affected children invariably develop disseminated bacille Calmette-Guérin (BCG) infection shortly after inoculation with live BCG vaccine (3–6). Rare survivors and nonvaccinated children develop severe infections caused by environmental non-tuberculous mycobacteria (NTM) in early childhood (4–8). Other clinical infectious diseases have been reported, but they are much less frequent and severe (9, 10). The pathogens identified include intracellular bacteria, such as Salmonella (7) and Listeria (6), and viruses, such as varicella-zoster virus (6, 10) and cytomegalovirus (5, 10). Mycobacterial granulomas are often multibacillary and in all cases are poorly delimited (no surrounding lymphocytes) and differentiated (no epithelioid or giant multinucleated phagocytic cells) (2). Affected children generally die in childhood because antibiotics do not give sustained remission of mycobacterial disease and IFN-γ therapy is ineffective in the absence of specific receptors (2). Bone marrow transplantation is the only curative treatment available (2, 6). A variety of IFNGR1 null recessive mutations are associated with complete IFNγR1 deficiency (2). They include nonsense (7) and splice (5, 6, 11) mutations and frameshift insertions (11) and deletions (3, 5, 6). The mutations affect different nucleotides in the IFNGR1 coding region, and neither founder nor recurrent mutations have been identified. However, all the reported mutations share two features. First, they are