ArticleNPJ genomic medicine2021
STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses.
Article in NPJ genomic medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 22 citations in OpenAlex.
- JAK-inhibitor treatment induces rapid yet incomplete immune reconstitution in STAT1 gain-of-function.Journal of human immunity · 2026Article
- Melanoma cell states shape spatial tumor-immune ecosystems to dictate the efficacy of anti-PD1 immunotherapy.Journal for immunotherapy of cancer · 2026Article
- Implications of virus-induced stress granules in tauopathies.Translational neurodegeneration · 2026Review
- STAT1-L351F is associated with enhanced interferon signaling and susceptibility toFrontiers in immunology · 2026Article
- A Child with Chronic Mucocutaneous Candidiasis Harbors a Novel Gain-of-Function Mutation in STAT1.Journal of clinical immunology · 2025Article
- Coinfection of Leprosy and Chronic Mucocutaneous Candidiasis in a Family with STAT1 Gain-of-Function Mutation.The American journal of tropical medicine and hygiene · 2025Article
- Case Report: Dual molecular diagnosis of gain-of-functionFrontiers in immunology · 2025Article
- Human inborn errors of immunity underlyingFrontiers in immunology · 2025Article
- Recapitulating primary immunodeficiencies with expanded potential stem cells: Proof of concept with STAT1 gain of function.The Journal of allergy and clinical immunology · 2024Article
- Retrospective identification of the first cord blood-transplanted severe aplastic anemia in aFrontiers in immunology · 2024Review
- Interferon autoantibodies as signals of a sick thymus.Frontiers in immunology · 2024Review
- Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.The Journal of experimental medicine · 2023Article
- CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins.Nucleic acids research · 2023Article
- Interferonopathies masquerading as non-Mendelian autoimmune diseases: pattern recognition for early diagnosis.Frontiers in pediatrics · 2023Review
- The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice.Frontiers in immunology · 2023Article
- Systems Immunology Analyses ofImmunoHorizons · 2022Article
- CRISPR/Cas therapeutic strategies for autosomal dominant disorders.The Journal of clinical investigation · 2022Review
- Immunoprofiling of monocytes in STAT1 gain-of-function chronic mucocutaneous candidiasis.Frontiers in immunology · 2022Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) is an autosomal dominant immune disorder marked by wide infectious predisposition, autoimmunity, vascular disease, and malignancy. Its molecular hallmark, elevated phospho-STAT1 (pSTAT1) following interferon (IFN) stimulation, is seen consistently in all patients and may not fully account for the broad phenotypic spectrum associated with this disorder. While over 100 mutations have been implicated in STAT1 GOF, genotype-phenotype correlation remains limited, and current overexpression models may be of limited use in gene expression studies. We generated heterozygous mutants in diploid HAP1 cells using CRISPR/Cas9 base-editing, targeting the endogenous STAT1 gene. Our models recapitulated the molecular phenotype of elevated pSTAT1, and were used to characterize the expression of five IFN-stimulated genes under a number of conditions. At baseline, transcriptional polarization was evident among mutants compared with wild type, and this was maintained following prolonged serum starvation. This suggests a possible role for unphosphorylated STAT1 in the pathogenesis of STAT1 GOF. Following stimulation with IFNα or IFNγ, differential patterns of gene expression emerged among mutants, including both gain and loss of transcriptional function. This work highlights the importance of modeling heterozygous conditions, and in particular transcription factor-related disorders, in a manner which accurately reflects patient genotype and molecular signature. Furthermore, we propose a complex and multifactorial transcriptional profile associated with various STAT1 mutations, adding to global efforts in establishing STAT1 GOF genotype-phenotype correlation and enhancing our understanding of disease pathogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.