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

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Title: An essential role for the Zn2+ transporter ZIP7 in B cell development
Authors: 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
Item Type: Journal Article
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.
Issue Date: 4-Feb-2019
Date of Acceptance: 5-Dec-2018
URI: http://hdl.handle.net/10044/1/66670
DOI: https://dx.doi.org/10.1038/s41590-018-0295-8
ISSN: 1529-2908
Publisher: Nature Research
Start Page: 350
End Page: 361
Journal / Book Title: Nature Immunology
Volume: 20
Copyright Statement: © 2019 The Author(s), under exclusive licence to Springer Nature America, Inc. The final publication is available at Springer Nature via https://dx.doi.org/10.1038/s41590-018-0295-8
Keywords: 1107 Immunology
Immunology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2019-02-04
Appears in Collections:Department of Medicine
Faculty of Medicine



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