STAT1 was first reported to be implicated in Immunodeficiency 31B, viral and mycobacterial infections, autosomal recessive, in 2003 (Dupuis et al., PMID: 12590259).
6 Variants (missence and frameshift) that have been reported in 7 probands in 5 publications are included in this curation (PMIDs: 12590259, 16585605, 20841510, 21772053, 32603902). The mechanism of pathogenicity is reported to be loss of function. Absence or impaired protein expression and the abolition or impaired cellular responses to IFN-γ, IFN-α/β, or IFN-λ, are demonstrated in the patients affected, leading to severe and potentially fatal mycobacterial and viral infections.
This gene- disease relationship is also supported by experimental evidence. Enriched STAT1 expression was detected in EBV-transformed B cells (PMID 23715323). Nuclear extracts of HeLaS3 cells treated with IFN-γ and IFN-α showed an increase in nuclear localization of STAT1 (PMID: 16319195). Activation of ISGF3 by IFN-α is shown to be impaired in cells of the patients homozygous with respect to the mutated STAT1 alleles. No IFN-stimulated response element (ISRE)–binding activity was detected in nuclear extracts from the mutated in response to IFN-α (PMID: 12590259). Electrophoretic mobility shift assay (EMSA) showed no γ-activated sequence (GAS)–binding proteins in response to IFN-γ in STAT1 mutant cell. A similar defect was shown in a patient with complete IFN-γR1 deficiency (PMID: 12590259).
In summary, there is definitive evidence supporting the relationship between STAT1 and immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld overtime.
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