Novel STAT1 Alleles in a Patient with Impaired Resistance to Mycobacteria

Abstract

Partial defects in interferon (IFN)-γ signaling lead to susceptibility to infections with nontuberculous mycobacteria. The receptors for IFN-α and IFN-γ activate components of the Janus kinase-signal transducer and activator of transcription (STAT) signaling pathway. Some defects in STAT1 mainly affect IFN-γ signaling, thus resulting in mendelian susceptibility to mycobacterial disease (MSMD). MSMD is a severe disease but patients show a favorable response to anti-mycobacterial chemotherapy. Other defects in STAT1 affect both IFN-α and IFN-γ signaling resulting in mycobacterial and lethal viral disease. We report here a patient with two novel STAT1 alleles, which in combination results in a recessive trait with partial STAT1 deficiency and mycobacterial disease. Cells from the patient did respond to mycobacterial antigen, but both the expression of STAT1 and phosphorylation of STAT1 in response to IFN-γ treatment were reduced. This is the first report of a mutation in the N-terminal part of STAT1 involved in causing mycobacterial disease.

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

“…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.…”

Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation

“…[13][14][15][16] Patients with heterozygous mutations of STAT1, unlike patients who are homozygous, display an impaired tyrosine phosphorylation or DNA-binding activity in response to IFN-␥ but retain a normal or partial response to IFN-␣ and are not susceptible to viral disease. 13,15,17 We describe here a patient with homozygous STAT1 splicing mutation leading to skipping of exon 3 who developed generalized mycobacterial infections and severe viral disease sustained by CMV. We report that the patient's cells display a complete defect of STAT1 DNA-binding activity after stimulation with IFN-␥ and IFN-␣ and fail to respond at even high doses of these cytokines.…”

SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ

“…1 Its actions are largely dependent on STAT1 activation by phosphorylation of tyrosine 701 as demonstrated by impaired antimicrobial immunity of patients and model organisms with defective STAT1 activation. [2][3][4][5][6] Several additional posttranslational modifications have been proposed to modulate the transcriptional activity of STAT1, 7 one modification of which is phosphorylation of serine residue 727 in the transactivation domain, 8,9 which is required for full-fledged IFN␥-dependent innate immunity. 10 In contrast, whether posttranslational modifications of STAT1 contribute to its negative regulation is less clear.…”