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

2019; Nature Portfolio; Volume: 20; Issue: 3 Linguagem: Inglês

10.1038/s41590-018-0295-8

1529-2916

Consuelo Anzilotti, David Swan, Bertrand Boisson, Mukta Deobagkar‐Lele, Catarina Oliveira, Pauline Chabosseau, Karin R. Engelhardt, Xijin Xu, Rui Chen, Luis Álvarez, Rolando Berlinguer‐Palmini, Katherine R. Bull, Eleanor Cawthorne, Adam P. Cribbs, Tanya L. Crockford, Tarana Singh Dang, Amy Fearn, Emma Fenech, Sarah Jill de Jong, B. Christoffer Lagerholm, S. Cindy, David Sims, Bert van den Berg, Yaobo Xu, Andrew J. Cant, Gary Kleiner, Timothy Ronan Leahy, M. Teresa de la Morena, Jennifer M. Puck, Ralph Shapiro, Mirjam van der Burg, J. Ross Chapman, John C. Christianson, Benjamin Davies, John A. McGrath, Stefan Przyborski, Mauro Santibáñez Koref, Stuart G. Tangye, Andreas Werner, Guy A. Rutter, Sergi Padilla‐Parra, Jean‐Laurent Casanova, Richard J. Cornall, Mary Ellen Conley, Sophie Hambleton,

Viral Infections and Immunology Research

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. Zinc is important for normal immunity but its mechanistic actions are poorly understood. Hambleton and colleagues identify defects in Zn2+ transport that underpin a novel human immunodeficiency characterized by loss of mature B cells.