A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

• Published in: The Journal of clinical investigation 2017-12, Vol.127 (12), p.4415-4420
• Main Authors: Hoyos-Bachiloglu, Rodrigo, Chou, Janet, Sodroski, Catherine N, Beano, Abdallah, Bainter, Wayne, Angelova, Magdalena, Al Idrissi, Eman, Habazi, Murad K, Alghamdi, Hamza Ali, Almanjomi, Fahd, Al Shehri, Mohamed, Elsidig, Nagi, Alaa Eldin, Morsi, Knipe, David M, AlZahrani, Mofareh, Geha, Raif S
• Format: Article
• Language: English
• Subjects: Bacteremia; Bacteremia - genetics; Bacteremia - immunology; Bacteremia - microbiology; Biomedical research; C-Terminus; Codons; Concise Communication; Cytomegalovirus; Cytomegalovirus - immunology; Cytomegalovirus Infections - genetics; Cytomegalovirus Infections - immunology; Disease susceptibility; Female; Fibroblasts; Fibroblasts - immunology; Fibroblasts - microbiology; Fibroblasts - virology; Gene deletion; Genetic aspects; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - immunology; Genetic Diseases, Inborn - microbiology; Genetic Diseases, Inborn - virology; Humans; Immunodeficiency; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - microbiology; Immunologic Deficiency Syndromes - virology; Immunotherapy; Interferon; Male; Mutation; Mycobacterium; Mycobacterium abscessus - immunology; Mycobacterium Infections, Nontuberculous - genetics; Mycobacterium Infections, Nontuberculous - immunology; Nuclear transport; Phosphorylation; Phosphorylation - genetics; Phosphorylation - immunology; Primary immunodeficiencies; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - immunology; Receptors, Interferon - genetics; Receptors, Interferon - immunology; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - immunology; Stat2 protein; STAT2 Transcription Factor - genetics; STAT2 Transcription Factor - immunology; Stop codon; Streptococcal Infections - genetics; Streptococcal Infections - immunology; Streptococcus; Viral infections; Viremia; Viremia - genetics; Viremia - immunology; Viremia - virology; Viridans Streptococci - immunology; Virus diseases; α-Interferon
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI93486

Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-γ receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 (IFNAR1*557Gluext*46), which encodes the IFN-α receptor signaling subunit. The IFNAR1*557Gluext*46 resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of IFNAR1*557Gluext*46 mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-α-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-α-stimulated genes critical for CMV immunity. Pretreatment with IFN-α failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-α-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.