| Literature DB >> 30718914 |
Consuelo Anzilotti1, David J Swan2, Bertrand Boisson3,4,5, Mukta Deobagkar-Lele1, Catarina Oliveira6, Pauline Chabosseau7, Karin R Engelhardt2, Xijin Xu1, Rui Chen2, Luis Alvarez6, Rolando Berlinguer-Palmini8, Katherine R Bull1, Eleanor Cawthorne1, Adam P Cribbs9, Tanya L Crockford1, Tarana Singh Dang2, Amy Fearn10, Emma J Fenech11, Sarah J de Jong3, B Christoffer Lagerholm1, Cindy S Ma12,13, David Sims9, Bert van den Berg10, Yaobo Xu14, Andrew J Cant15, Gary Kleiner16, T Ronan Leahy17, M Teresa de la Morena18, Jennifer M Puck19,20, Ralph S Shapiro21, Mirjam van der Burg22, J Ross Chapman6, John C Christianson11, Benjamin Davies6, John A McGrath23, Stefan Przyborski24, Mauro Santibanez Koref14, Stuart G Tangye12,13, Andreas Werner10, Guy A Rutter7, Sergi Padilla-Parra6,25,26, Jean-Laurent Casanova3,4,5,27,28, Richard J Cornall29, Mary Ellen Conley30, Sophie Hambleton31,32.
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.Entities:
Mesh：
Substances：
Year: 2019 PMID： 30718914 PMCID： PMC6561116 DOI： 10.1038/s41590-018-0295-8
Source DB: PubMed Journal: Nat Immunol ISSN： 1529-2908 Impact factor: 25.606