A Novel STAT1 Mutation Associated with Disseminated Mycobacterial Disease

Abstract

STAT1 is a key component of Interferon (IFN)-γ and IFN-α signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961 T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GAS-luciferase activity, and expression of IFN-γ target genes are reduced. IFN-α driven ISRE response, but not IFN-α driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-α induced immune function.

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

“…Indeed, AD STAT1 mutations impairing STAT1 phosphorylation have been shown to underlie the pathogenesis of MSMD. [14][15][16][17] Furthermore, AD mutations that cause gains of phosphorylation because they impair the nuclear dephosphorylation of STAT1 have been identified in patients with chronic mucocutaneous candidiasis. [30][31][32][33][34] The Y701C mutant STAT1 protein displayed a complete abolition of Y701 phosphorylation and downstream events, such as the nuclear translocation and transcriptional activities of GAS and ISRE.…”

“…ISG induction has been intensively investigated in EBV-B cells, 15,17 but this is the first study to investigate the induction of ISG in primary cells from patients. Both EBV-B cell lines and primary monocytes from the patients showed severe impairment of CXCL9 induction.…”

“…Figure 1A shows previously identified heterozygous or biallelic STAT1 mutations causing AD or AR genetic susceptibility to mycobacterial diseases. [14][15][16][17][18][19][20][21][22] The Y701C mutation affects the Y701 residue, the site of tyrosine phosphorylation in the STAT1 tail segment domain, a residue crucial for the activation of this molecule.…”

“…The M654K and K673R mutations impair the tyrosine phosphorylation of STAT1, whereas the K637E mutation impairs both STAT1 phosphorylation and GAF-DNA binding. 16,17 These mutations are loss-offunction or hypomorphic and have been shown to exert a dominant-negative effect on wild-type STAT1 for IFN-γ responses.…”

“…[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.…”