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An essential role for the Zn2+ transporter ZIP7 in B cell development
- Anzilotti, Consuelo;
- Swan, David J;
- Boisson, Bertrand;
- Deobagkar-Lele, Mukta;
- Oliveira, Catarina;
- Chabosseau, Pauline;
- Engelhardt, Karin R;
- Xu, Xijin;
- Chen, Rui;
- Alvarez, Luis;
- Berlinguer-Palmini, Rolando;
- Bull, Katherine R;
- Cawthorne, Eleanor;
- Cribbs, Adam P;
- Crockford, Tanya L;
- Dang, Tarana Singh;
- Fearn, Amy;
- Fenech, Emma J;
- de Jong, Sarah J;
- Lagerholm, B Christoffer;
- Ma, Cindy S;
- Sims, David;
- van den Berg, Bert;
- Xu, Yaobo;
- Cant, Andrew J;
- Kleiner, Gary;
- Leahy, T Ronan;
- de la Morena, M Teresa;
- Puck, Jennifer M;
- Shapiro, Ralph S;
- van der Burg, Mirjam;
- Chapman, J Ross;
- Christianson, John C;
- Davies, Benjamin;
- McGrath, John A;
- Przyborski, Stefan;
- Santibanez Koref, Mauro;
- Tangye, Stuart G;
- Werner, Andreas;
- Rutter, Guy A;
- Padilla-Parra, Sergi;
- Casanova, Jean-Laurent;
- Cornall, Richard J;
- Conley, Mary Ellen;
- Hambleton, Sophie
- et al.
Published Web Location
https://doi.org/10.1038/s41590-018-0295-8Abstract
Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.
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