A heterozygous dominant-negative mutation in the coiled-coil domain of STAT1 is the cause of autosomal-dominant Mendelian susceptibility to mycobacterial diseases.
Moreover, 6% of patients with chronic mucocutaneous candidiasis with a GOF STAT1 mutation have mycobacterial disease, obscuring the functional significance of the identified STAT1 mutations.
Autosomal partial dominant (PD) interferon-γ receptor 1 (IFN-γR1) deficiency is the most frequent abnormality affecting the group of MSMD patients leading to impaired response of IFN-γ.
Mutations conferring Mendelian susceptibility to mycobacterial diseases have been identified in the regions of the STAT1 gene encoding the tail segment, DNA-binding domain and SH2 domain.
Interestingly, both patients displayed multifocal osteomyelitis, which is often seen in patients with Mendelian susceptibility to mycobacterial diseases with autosomal dominant partial IFN-γR1 deficiency.
Interferon-γ receptor-1 (IFNγR1) deficiency is caused by mutations in the IFNγR1 gene and is characterized mainly by susceptibility to mycobacterial disease.
Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ.
RP-IFN-γR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases.
Mutations of the gene encoding the signal transducing molecule STAT1, which impairs the ability to respond to IFNgamma, and mutations of the gene encoding TYK2 (which is associated with a failure to respond to IL12), are both rare genetic defects predisposing to mycobacterial infections.
Disorders of IFN-gamma production, caused by IL12B, IL12RB1, and specific NEMO mutations, or of IFN-gamma responses, caused by IFNGR1, IFNGR2, and dominant STAT1 mutations, confer predisposition to mycobacterial disease in patients resistant to most viruses.
We identified a novel dominant mutation in IFNGR1, designated 774del4, which produced a truncated form of IFNgammaR1 in a patient with recurrent mycobacterial infections.
These primary immunodeficiencies are caused by germline mutations in seven genes: ELA2, encoding a neutrophil elastase, and GFI1, encoding a regulator of ELA2 (mutations associated with severe congenital neutropenia); CXCR4, encoding a chemokine receptor (warts, hypogammaglobulinemia, infections and myelokathexis syndrome); LCRR8, encoding a key protein for B-cell development (agammaglobulinemia); IFNGR1, encoding the ligand-binding chain of the interferon-gamma receptor; STAT1, encoding the signal transducer and activator of transcription 1 downstream from interferon-gammaR1 (Mendelian susceptibility to mycobacterial diseases); and IKBA, encoding IkappaBalpha, the inhibitor alpha of NF-kappaB (anhidrotic ectodermal dysplasia with immunodeficiency).
Human mutations in IFN-gamma receptor-1 (IFN-gammaR1), IFN-gammaR2, IL-12p40, IL-12 receptor-beta1, signal transducer and activator of transcription-1, and nuclear factor-kappaB essential modulator are analyzed in the context of genetic susceptibility to mycobacterial diseases.
These primary immunodeficiencies are caused by germline mutations in seven genes: ELA2, encoding a neutrophil elastase, and GFI1, encoding a regulator of ELA2 (mutations associated with severe congenital neutropenia); CXCR4, encoding a chemokine receptor (warts, hypogammaglobulinemia, infections and myelokathexis syndrome); LCRR8, encoding a key protein for B-cell development (agammaglobulinemia); IFNGR1, encoding the ligand-binding chain of the interferon-gamma receptor; STAT1, encoding the signal transducer and activator of transcription 1 downstream from interferon-gammaR1 (Mendelian susceptibility to mycobacterial diseases); and IKBA, encoding IkappaBalpha, the inhibitor alpha of NF-kappaB (anhidrotic ectodermal dysplasia with immunodeficiency).
Recessive complete and dominant partial IFNgammaR1 deficiencies have related clinical phenotypes, but are distinguishable by age at onset, dissemination, and clinical course of mycobacterial diseases.
Human mutations in IFN-gamma receptor-1 (IFN-gammaR1), IFN-gammaR2, IL-12p40, IL-12 receptor-beta1, signal transducer and activator of transcription-1, and nuclear factor-kappaB essential modulator are analyzed in the context of genetic susceptibility to mycobacterial diseases.