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

• DOI: 10.1038/s41590-018-0295-8
• Publication Date: 2019-02-04T17:03:59Z
• Authors: Consuelo Anzilotti; David J. Swan; Bertrand Boisson; Mukta Deobagkar-Lele; Catarina Oliveira; Pauline Chabosseau; Karin R. Engelhardt; Xijin Xu; Rui Chen; Luis Alvarez; Rolando Berlingue...; Katherine R. Bull; Eleanor Cawthorne; Adam P. Cribbs; Tanya L. Crockford; Tarana Singh Dang; Amy Fearn; Emma J. Fenech; Sarah J. de Jong; B. Christoffer La...; Cindy S. Ma; David Sims; Bert van den Berg; Yaobo Xu; Andrew J. Cant; Gary Kleiner; T. Ronan Leahy; M. Teresa de la M...; Jennifer M. Puck; Ralph S. Shapiro; Mirjam van der Burg; J. Ross Chapman; John C. Christianson; Benjamin Davies; John A. McGrath; Stefan Przyborski; Mauro Santibanez ...; Stuart G. Tangye; Andreas Werner; Guy A. Rutter; Sergi Padilla-Parra; Jean-Laurent Casa...; Richard J. Cornall; Mary Ellen Conley; Sophie Hambleton
• Keywords: Male; 0301 basic medicine; 570; EMC MM-02-72-02; 571; 1.1 Normal biological development and functioning; Immunology; 610; Mice, Transgenic; Inbred C57BL; Endoplasmic Reticulum; Transgenic; EMC MM-02-72-01; Mice; 03 medical and health sciences; Cytosol; Agammaglobulinemia; 616; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; Child; Preschool; Cation Transport Proteins; Pediatric; B-Lymphocytes; Biomedical and Clinical Sciences; Animal; Gene Expression Profiling; Infant; Biological Sciences; Pedigree; Mice, Inbred C57BL; Disease Models, Animal; Zinc; 1107 Immunology; Biochemistry and cell biology; Child, Preschool; Disease Models; Mutation; Female; Biochemistry and Cell Biology

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.