ArticleThe Journal of allergy and clinical immunology2017
Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants.
Article in The Journal of allergy and clinical immunology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review.Frontiers in immunology · 2021Pooled it
- From variants to answers: The evolution of genetic counseling in IEI.Journal of human immunity · 2026Review
- Disordered protein LAT encodes relative levels of signaling pathways in T cell activation.Science (New York, N.Y.) · 2026Article
- Investigation of the transcriptional impact of rare germline JAK/STAT variants found in a Tyrolean alpine community.BMC genomics · 2025Article
- A Child with Chronic Mucocutaneous Candidiasis Harbors a Novel Gain-of-Function Mutation in STAT1.Journal of clinical immunology · 2025Article
- PreMode predicts mode-of-action of missense variants by deep graph representation learning of protein sequence and structural context.Nature communications · 2025Article
- A novel loss-of-function variant inFrontiers in cellular and infection microbiology · 2025Article
- A Norwegian cohort with STAT1-related disease - further expanding the clinical phenotype.Frontiers in immunology · 2025Article
- Uncovering hidden immune defects in childhood granulomatous disorders: a case report.Frontiers in immunology · 2025Article
- Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.Journal of clinical immunology · 2024Article
- Qualitative Immunoglobulin Deficiency Causes Bacterial Infections in Patients with STAT1 Gain-of-Function Mutations.Journal of clinical immunology · 2024Article
- Case report: A novelFrontiers in immunology · 2024Article
- A novel interface between the N-terminal and coiled-coil domain of STAT1 functions in an auto-inhibitory manner.Cell communication and signaling : CCS · 2023Article
- Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds.Journal of clinical immunology · 2023Article
- Inborn errors of immunity with loss- and gain-of-function germline mutations in STAT1.Clinical and experimental immunology · 2023Review
- Genetic and Functional Identifying of Novel STAT1 Loss-of-Function Mutations in Patients with Diverse Clinical Phenotypes.Journal of clinical immunology · 2022Article
- STAT1 and Its Crucial Role in the Control of Viral Infections.International journal of molecular sciences · 2022Review
- JAK inhibition in a patient with a STAT1 gain-of-function variant reveals STAT1 dysregulation as a common feature of aplastic anemia.Med (New York, N.Y.) · 2022Article
- Gain-of-function STAT1 mutation and visceral leishmaniasis.Einstein (Sao Paulo, Brazil) · 2022Article
- A novel STAT1 loss-of-function mutation associated with Mendelian susceptibility to mycobacterial disease.Frontiers in cellular and infection microbiology · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
29 authors at 11 institutions in 5 countries.
Funding
Abstract
backgroundGermline heterozygous mutations in human signal transducer and activator of transcription 1 (STAT1) can cause loss of function (LOF), as in patients with Mendelian susceptibility to mycobacterial diseases, or gain of function (GOF), as in patients with chronic mucocutaneous candidiasis. LOF and GOF mutations are equally rare and can affect the same domains of STAT1, especially the coiled-coil domain (CCD) and DNA-binding domain (DBD). Moreover, 6% of patients with chronic mucocutaneous candidiasis with a GOF STAT1 mutation have mycobacterial disease, obscuring the functional significance of the identified STAT1 mutations. Current computational approaches, such as combined annotation-dependent depletion, do not distinguish LOF and GOF variants.
objectiveWe estimated variations in the CCD/DBD of STAT1.
methodsWe mutagenized 342 individual wild-type amino acids in the CCD/DBD (45.6% of full-length STAT1) to alanine and tested the mutants for STAT1 transcriptional activity.
resultsOf these 342 mutants, 201 were neutral, 30 were LOF, and 111 were GOF mutations in a luciferase assay. This assay system correctly estimated all previously reported LOF mutations (100%) and slightly fewer GOF mutations (78.1%) in the CCD/DBD of STAT1. We found that GOF alanine mutants occurred at the interface of the antiparallel STAT1 dimer, suggesting that they destabilize this dimer. This assay also precisely predicted the effect of 2 hypomorphic and dominant negative mutations, E157K and G250E, in the CCD of STAT1 that we found in 2 unrelated patients with Mendelian susceptibility to mycobacterial diseases.
conclusionThe systematic alanine-scanning assay is a useful tool to estimate the GOF or LOF status and the effect of heterozygous missense mutations in STAT1 identified in patients with severe infectious diseases, including mycobacterial and fungal diseases.
Indexed as
Identifiers
What OpenQuestion holds
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.