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| Status |
Public on Nov 19, 2018 |
| Title |
Human immunodeficiency reveals the Zn2+-dependence of B cell development |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Despite the known importance of zinc for human immunity, molecular insights into its roles remain limited. Here we report a novel autosomal recessive disease characterised by early-onset infections, absent B cells and agammaglobulinaemia in five unrelated families. The immunodeficiency results from a series of hypomorphic and null alleles of SLC39A7, which encodes the endoplasmic-reticulum-to-cytoplasm zinc transporter, ZIP7. Using CRISPR-Cas9 editing and homologous recombination we have modelled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic lethality, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited increased phosphatase activity and decreased phosphorylation of signalling molecules that lie downstream of the pre-B and B cell receptors. Our findings highlight a specific role for Zn2+ in modulating B cell receptor signal strength and positive selection, and suggest how Zn2+ could modulate outcome in a variety of signalling contexts.
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| Overall design |
We constructed 40 RNA-seq libraries; 4 stages of B cells, 2 conditions (WT and mutant), 5 replicates. 5 WT and 5 P198A/P198A mutant staight chimeras mice were stained and sorted for FrB,C,D,E in BM. 100 cells each sample, processed by Smartseq2. Sequenced by HiSeq4000.
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| Contributor(s) |
Cribbs AP, Xu X, Anzilotti C, Cornall RJ |
| Citation missing |
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| |
| Submission date |
Dec 18, 2017 |
| Last update date |
Mar 19, 2019 |
| Contact name |
Adam Cribbs |
| E-mail(s) |
[email protected]
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| Organization name |
University of Oxford
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| Department |
NDORMS
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| Street address |
Windmill Road
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| City |
Oxford |
| ZIP/Postal code |
OX37LD |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (40)
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| Relations |
| BioProject |
PRJNA422757 |
| SRA |
SRP126928 |
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