Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Nov;40(8):1065-1081.
doi: 10.1007/s10875-020-00847-x. Epub 2020 Aug 27.

Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy

Satoshi Okada  1 , Takaki Asano  2   3 , Kunihiko Moriya  4   5 , Stephanie Boisson-Dupuis  3   4   5 , Masao Kobayashi  2 , Jean-Laurent Casanova  3   4   5   6   7 , Anne Puel  8   9   10
Affiliations
Review

Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy

Satoshi Okada et al. J Clin Immunol. 2020 Nov.

Abstract

Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.

Keywords: Mendelian susceptibility to mycobacterial diseases; STAT1; chronic mucocutaneous candidiasis; gain-of-function; virus.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest

The authors declare that they have no relevant conflicts of interest.

Figures

Figure 1
Figure 1
Known GOF and LOF mutations of STAT1 GOF mutations are shown in red, while LOF mutations that cause AD-STAT1 deficiency, AR-STAT1 complete deficiency and AR-STAT1 partial deficiency are shown in brown, purple and green, respectively. N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), linker (L) domain, SH2 domain (SH2D), tail segment domain (TSD), transactivation domain (TAD).
Figure 2
Figure 2
Population genetics for STAT1. CADD score (y-axis) vs. minor allele frequency (MAF, x-axis) for all the heterozygous variants of STAT1 found in gnomAD (blue) and STAT1-GOF mutations (red).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dale TC, Imam AM, Kerr IM, Stark GR. Rapid activation by interferon alpha of a latent DNA-binding protein present in the cytoplasm of untreated cells. Proc Natl Acad Sci U S A. 1989;86(4):1203–7. - PMC - PubMed
    1. Levy DE, Kessler DS, Pine R, Darnell JE Jr. Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Dev. 1989;3(9):1362–71. - PubMed
    1. Darnell JE Jr., Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264(5164):1415–21. - PubMed
    1. Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293–322. - PubMed
    1. Subramaniam PS, Torres BA, Johnson HM. So many ligands, so few transcription factors: a new paradigm for signaling through the STAT transcription factors. Cytokine. 2001;15(4):175–87. - PubMed

Publication types

MeSH terms