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An essential role for the Zn(2+) transporter ZIP7 in B cell development


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 Zn(2+) in modulating B cell receptor signal strength and positive selection.

Type Journal
ISBN 1529-2916 (Electronic) 1529-2908 (Linking)
Authors Anzilotti, C.; Swan, D. J.; Boisson, B.; Deobagkar-Lele, M.; Oliveira, C.; Chabosseau, P.; Engelhardt, K. R.; Xu, X.; Chen, R.; Alvarez, L.; Berlinguer-Palmini, R.; Bull, K. R.; Cawthorne, E.; Cribbs, A. P.; Crockford, T. L.; Dang, T. S.; Fearn, A.; Fenech, E. J.; de Jong, S. J.; Lagerholm, B. C.; Ma, C. S.; Sims, D.; van den Berg, B.; Xu, Y.; Cant, A. J.; Kleiner, G.; Leahy, T. R.; de la Morena, M. T.; Puck, J. M.; Shapiro, R. S.; van der Burg, M.; Chapman, J. R.; Christianson, J. C.; Davies, B.; McGrath, J. A.; Przyborski, S.; Santibanez Koref, M.; Tangye, S. G.; Werner, A.; Rutter, G. A.; Padilla-Parra, S.; Casanova, J. L.; Cornall, R. J.; Conley, M. E.; Hambleton, S.
Responsible Garvan Author Prof Stuart Tangye
Published Date 2019-03-01
Published Volume 20
Published Issue 3
Published Pages 350-361
Status Published in-print
DOI 10.1038/s41590-018-0295-8
URL link to publisher's version