Novel STAT1 Alleles in Otherwise Healthy Patients with Mycobacterial Disease

Abstract

The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)–induced gamma-activating factor–mediated immunity and interferon alpha (IFNA)–induced interferon-stimulated genes factor 3–mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor–mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3–mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding.

JAK-STAT Signaling: From Interferons to Cytokines

“…Gene targeting studies confirmed the pivotal role that Stat1 plays in the biological response to both type I and type II IFNs (20,21). Consistent with this, humans expressing Stat1 mutants exhibit increased susceptibility to viral and bacterial infections (22). Intriguingly, Stat1 target genes appear to promote inflammation and antagonize proliferation.…”

Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis

“…[14][15][16][17] Six mutations, E320Q, Q463H, K637E, M654K, K673R and L706S in STAT1, have been reported ( Figure 1A). [14][15][16][17] The L706S mutation affects the tail segment domain of STAT1, abolishing phosphorylation at Y701. 14 The E320Q and Q463H mutations affect the DNA-binding domain.…”

“…14 The E320Q and Q463H mutations affect the DNA-binding domain. 15 They have no effect on STAT1 phosphorylation, but modify the DNA-binding capacity of GAF, impairing January 6, 2013. Manuscript accepted on April 5, 2013.…”

Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation

“…1A). However, the critical residues for DNA binding and phosphorylation have been identified as Gln-463 and Tyr-701, respectively (5,6). In contrast, GOF mutations clearly accumulate in the CCD and the DBD (Fig.…”

“…1A). The loss-of-function (LOF) 2 mutations have been associated with the pathogenesis of Mendelian susceptibility to mycobacterial disease, which is a rare syndrome characterized by infections with weakly virulent mycobacteria (5,6). On the other hand, its gain-of-function (GOF) mutations exhibit different immunological defects.…”