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An essential role for the Zn2+ transporter ZIP7 in B cell development.

Anzilotti, Consuelo and Swan, David J. and Boisson, Bertrand and Deobagkar-Lele, Mukta and Oliveira, Cathy and Chabosseau, Pauline and Engelhardt, Karin R. and Xu, Xijin and Chen, Rui and Alvarez, Luis and Berlinguer-Palmini, Rolando and Bull, Katherine R. and Cawthorne, Eleanor and Cribbs, Adam P. and Crockford, Tanya L. and Dang, Tarana Singh and Fearn, Amy and Fenech, Emma J. and de Jong, Sarah J. and Lagerholm, B.Christoffer and Ma, Cindy S. and Sims, David and van den Berg, Bert and Xu, Yaobo and Cant, Andrew J. and Kleiner, Gary and Leahy, T. Ronan and de la Morena, M. Teresa and Puck, Jennifer M. and Shapiro, Ralph S. and van der Burg, Mirjam and Chapman, J. Ross and Christianson, John C. and Davies, Ben and McGrath, John A. and Przyborski, Stefan and Koref, Mauro Santibanez and Tangye, Stuart G. and Werner, Andreas and Rutter, Guy A. and Padilla-Parra, Sergi and Casanova, Jean-Laurent and Cornall, Richard J. and Conley, Mary Ellen and Hambleton, Sophie (2019) 'An essential role for the Zn2+ transporter ZIP7 in B cell development.', Nature immunology., 20 . pp. 350-361.


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.

Item Type:Article
Full text:(AM) Accepted Manuscript
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Date accepted:05 December 2018
Date deposited:16 January 2019
Date of first online publication:04 February 2019
Date first made open access:04 August 2019

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