Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency
General Information (adopted from Orphanet):
Synonyms, Signs:
STAT1 DEFICIENCY, AUTOSOMAL RECESSIVE
MSMD due to partial signal transducer and activator of transcription 1 deficiency
MSMD due to partial STAT1 deficiency
Mendelian susceptibility to mycobacterial diseases due to partial signal transducer and activator of transcription 1 deficiency
Dupuis et al. (2003) studied 2 unrelated infants, P1 and P2, with a clinical syndrome of severe mycobacterial and viral diseases not consistent with any known primary immunodeficiency. Infant P1 died of disseminated disease with recurrent encephalitis caused ... Dupuis et al. (2003) studied 2 unrelated infants, P1 and P2, with a clinical syndrome of severe mycobacterial and viral diseases not consistent with any known primary immunodeficiency. Infant P1 died of disseminated disease with recurrent encephalitis caused by herpes simplex virus-1; infant P2 died of a viral-like illness, but viral cultures and serologies could not be done. Both children had developed disseminated BCG vaccine infection (see 209950), which was in remission after antibiotic treatment when symptoms of viral infection appeared. STAT1 was considered a likely candidate gene, given its involvement in both the IFN-gamma (IFNG; 147570) and IFN-alpha (see 147660)/beta (see 147640) signaling pathways. Chapgier et al. (2006) reported a 3-month-old infant of first-cousin Pakistani parents who presented with disseminated BCG infection following BCG vaccination. The patient had a diffuse maculopapular rash, massive hepatosplenomegaly, and respiratory distress. In spite of antimycobacterial and antiinflammatory treatment and eventual bone marrow transplantation, the patient died of multiorgan failure after numerous viral infections, including a fulminant Epstein-Barr virus infection, 3 months after transplantation. The patient's mononuclear cells were unable to produce IL12 (see 161560) or IFNG above background levels after stimulation with BCG, and BCG-induced TNF (191160) production was also suppressed. Western blot analysis showed absent expression of STAT1, but normal expression of STAT3 (102582). Kong et al. (2010) reported 2 consanguineous Saudi Arabian sibs with autosomal recessive partial STAT1 deficiency who suffered multiple infectious episodes with low virulence mycobacterial pathogens and viruses. The male proband, who was not BCG vaccinated, developed disseminated M. avium disease at 6 years of age and improved with treatment. At 8 years of age, he developed disseminated varicella, followed by candidiasis. Another bout of M. avium disease in the central nervous system occurred at 9 years of age, leading to seizures and eventual blindness. The patient remained hospitalized at the time of report. His sister was BCG vaccinated at birth and developed disseminated disease. She died at 3 years of age from septic shock.
In 2 unrelated infants, P1 and P2, with a clinical syndrome of severe mycobacterial and viral diseases, Dupuis et al. (2003) identified homozygosity for point mutations in the STAT1 gene (600555.0002; 600555.0003). STAT1 interacts with STAT2 (600556) and ... In 2 unrelated infants, P1 and P2, with a clinical syndrome of severe mycobacterial and viral diseases, Dupuis et al. (2003) identified homozygosity for point mutations in the STAT1 gene (600555.0002; 600555.0003). STAT1 interacts with STAT2 (600556) and p48/IRF9 (147574) to form the transcription factor interferon-stimulated gene factor-3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. A heterozygous STAT1 mutation that impaired GAF but not ISGF3 activation had been found in individuals with mycobacterial disease (600555.0001). The infants described by Dupuis et al. (2003) represented the first examples of deleterious mutations in the IFN-alpha/beta signaling pathway. Like individuals with deficiency of IFN-gamma receptor (see 107470), both infants suffered from mycobacterial disease, but unlike individuals with IFN-gamma receptor deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the 2 infants. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease. In the patient they reported with complete STAT1 deficiency, Chapgier et al. (2006) identified a homozygous 1-bp insertion at nucleotide 1928 of the STAT1 gene (600555.0006), which led to a frameshift and a stop codon at nucleotides 1936 to 1938. EMSA analysis showed lack of GAS- and ISRE-binding protein expression after IFNG and IFNA stimulation. FACS analysis demonstrated lack of HLA class II expression after IFNG stimulation. IFNA was unable to suppress replication of herpes simplex or vesicular stomatitis virus replication in the patient's B-cell lines. Chapgier et al. (2006) concluded that STAT1 is critical to both viral and intracellular bacterial infections. In the 2 consanguineous sibs they reported with autosomal recessive partial STAT1 deficiency, Kong et al. (2010) identified a homozygous lys201-to-asn (K201N; 600555.0007) mutation in the STAT1 gene. The mutation caused abnormal splicing out of exon 8 from most STAT1 mRNAs, thereby decreasing STAT1 protein levels by approximately 70%. The K201N mutant STAT1 protein was not intrinsically deleterious, in terms of tyrosine phosphorylation, dephosphorylation, homodimerization into GAF, heterotrimerization into ISGF3, binding to DNA elements, and activation of transcription. Activation of GAF and ISGF3 was impaired only at early time points in patient cells, and delayed responses were normal. Kong et al. (2010) concluded that early cellular responses to IFNs are critically dependent on the amount of STAT1 and are essential for control of mycobacterial and viral infections.