1. An essential role for the Zn2+ transporter ZIP7 in B cell development
- Author
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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, and Hambleton, Sophie
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Prevention ,Genetics ,Brain Disorders ,Underpinning research ,Aetiology ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Agammaglobulinemia ,Animals ,B-Lymphocytes ,Cation Transport Proteins ,Child ,Preschool ,Cytosol ,Disease Models ,Animal ,Endoplasmic Reticulum ,Female ,Gene Expression Profiling ,Humans ,Infant ,Male ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Mutation ,Pedigree ,Zinc ,Immunology ,Biochemistry and cell biology - Abstract
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.
- Published
- 2019