Torrance, Robert;
McKenna, Alexander J;
King, Catherine;
McDowell, Joe;
O’Callaghan, Eleanor;
Maimaris, Jesmeen;
Albuquerque, Adriana S;
... Burns, Siobhan O; + view all
(2025)
The T385M STAT1 gain-of-function mutation confers the most severe disease outcomes.
Frontiers in Immunology
, 16
, Article 1717692. 10.3389/fimmu.2025.1717692.
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Abstract
BACKGROUND: Gain-of-function (GOF) mutations in STAT1 cause a combined immunodeficiency characterized by chronic mucocutaneous candidiasis (CMC), recurrent infections, and autoimmunity. Mutations in the DNA-binding domain (DBD) have previously been associated with poor outcomes, but the contributions of specific variants to clinical phenotype remain unexplored. METHODS: We performed a systematic literature review to identify patients with confirmed STAT1 GOF mutations, integrating new cases with a previously reported international cohort. Clinical and genetic data were analyzed at both domain and mutation level to define genotype-phenotype correlations. RESULTS: A total of 533 unique patients from 36 countries were identified, harboring 135 distinct mutations. As previously reported, DBD mutations were associated with increased risk of systemic infections, bronchiectasis, autoimmunity, and reduced survival. However, mutation-level stratification revealed that the T385M variant accounted for much of this effect. Compared with both other DBD mutations and mutations elsewhere in STAT1, T385M conferred significantly higher rates of infection, bronchiectasis, autoimmunity, and premature death (p < 0.001). Conversely, certain coiled-coil (CC) domain mutations, such as R274Q, were associated with milder disease and improved survival. CONCLUSIONS: Our findings demonstrate that the adverse prognosis previously ascribed to DBD mutations in STAT1 GOF is predominantly driven by the T385M variant. Mutation-specific, rather than domain-level, stratification is therefore essential for accurate risk assessment and clinical management. In particular, patients predicted to have severe disease, such as those with the T385M mutation should be considered early for curative interventional therapies such as stem cell transplant or gene therapy.
| Type: | Article |
|---|---|
| Title: | The T385M STAT1 gain-of-function mutation confers the most severe disease outcomes |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fimmu.2025.1717692 |
| Publisher version: | https://doi.org/10.3389/fimmu.2025.1717692 |
| Language: | English |
| Additional information: | © 2025 Torrance, McKenna, King, McDowell, O’Callaghan, Maimaris, Albuquerque, Pearce, Morris and Burns. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | STAT1, gain-of-function, primary immunodeficiency, mutation, phenotype, outcome |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10218431 |
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