An essential role for the Zn2+ transporter ZIP7 in B cell development.
Anzilotti C., Swan DJ., Boisson B., Deobagkar-Lele M., Oliveira C., Chabosseau P., Engelhardt KR., Xu X., Chen R., Alvarez L., Berlinguer-Palmini R., Bull KR., Cawthorne E., Cribbs AP., Crockford TL., Dang TS., Fearn A., Fenech EJ., de Jong SJ., Lagerholm BC., Ma CS., Sims D., van den Berg B., Xu Y., Cant AJ., Kleiner G., Leahy TR., de la Morena MT., Puck JM., Shapiro RS., van der Burg M., Chapman JR., Christianson JC., Davies B., McGrath JA., Przyborski S., Santibanez Koref M., Tangye SG., Werner A., Rutter GA., Padilla-Parra S., Casanova J-L., Cornall RJ., Conley ME., Hambleton S.
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.