ArticleImmunology2014
A novel Zap70 mutation with reduced protein stability demonstrates the rate-limiting threshold for Zap70 in T-cell receptor signalling.
Article in Immunology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Decoding the deactivation mechanism of R192W mutation of ZAP-70 using molecular dynamics simulations and binding free energy calculations.Journal of molecular modeling · 2023Article
- Combined immunodeficiency caused by pathogenic variants in theFrontiers in immunology · 2023Article
- Novel Compound Heterozygous Mutations in ZAP70 Leading to a SCID Phenotype with Normal Downstream In vitro Signaling.Journal of clinical immunology · 2021Article
- Mutations inAnimals : an open access journal from MDPI · 2020Article
- ZAP-70 in Signaling, Biology, and Disease.Annual review of immunology · 2018Review
- Seasonal immunoregulation in a naturally-occurring vertebrate.BMC genomics · 2016Article
- Quantitative reduction of the TCR adapter protein SLP-76 unbalances immunity and immune regulation.Journal of immunology (Baltimore, Md. : 1950) · 2015Article
- A ZAP-70 kinase domain variant prevents thymocyte-positive selection despite signalling CD69 induction.Immunology · 2014Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Loss of ζ-associated protein 70 (Zap70) results in severe immunodeficiency in humans and mice because of the critical role of Zap70 in T-cell receptor (TCR) signalling. Here we describe a novel mouse strain generated by N-ethyl-N-nitrosourea mutagenesis, with the reduced protein stability (rps) mutation in Zap70. The A243V rps mutation resulted in decreased Zap70 protein and a reduced duration of TCR-induced calcium responses, equivalent to that induced by a 50% decrease in catalytically active Zap70. The reduction of signalling through Zap70 was insufficient to substantially perturb thymic differentiation of conventional CD4 and CD8 T cells, although Foxp3(+) regulatory T cells demonstrated altered thymic production and peripheral homeostasis. Despite the mild phenotype, the Zap70(A243V) variant lies just above the functional threshold for TCR signalling competence, as T cells relying on only a single copy of the Zap70(rps) allele for TCR signalling demonstrated no intracellular calcium response to TCR stimulation. This addition to the Zap70 allelic series indicates that a rate-limiting threshold for Zap70 protein levels exists at which signalling capacity switches from nearly intact to effectively null.
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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.