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

Consuelo Anzilotti; David J. Swan; Bertrand Boisson; Mukta Deobagkar-Lele; Catarina Oliveira; Pauline Chabosseau; Karin R. Engelhardt; Xijin Xu; Rui Chen; Luis Alvarez; Rolando Berlinguer-Palmini; 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 Lagerholm; Cindy S. Ma; David Sims; Bert van den Berg; Yaobo Xu; Andrew J. Cant; Gary Kleiner; T. Ronan Leahy; M. Teresa de la Morena; 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 Koref; Stuart G. Tangye; Andreas Werner; Guy A. Rutter; Sergi Padilla-Parra; Jean Laurent Casanova; Richard J. Cornall; Mary Ellen Conley; Sophie Hambleton

doi:10.1038/s41590-018-0295-8

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

Consuelo Anzilotti, David J. Swan, Bertrand Boisson, Mukta Deobagkar-Lele, Catarina Oliveira, Pauline Chabosseau, Karin R. Engelhardt, Xijin Xu, Rui Chen, Luis Alvarez, Rolando Berlinguer-Palmini, 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 LagerholmCindy S. Ma, David Sims, Bert van den Berg, Yaobo Xu, Andrew J. Cant, Gary Kleiner, T. Ronan Leahy, M. Teresa de la Morena, 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 Koref, Stuart G. Tangye, Andreas Werner, Guy A. Rutter, Sergi Padilla-Parra, Jean Laurent Casanova, Richard J. Cornall, Mary Ellen Conley, Sophie Hambleton

Research output: Contribution to journal › Article › peer-review

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

Original language	English (US)
Pages (from-to)	350-361
Number of pages	12
Journal	Nature immunology
Volume	20
Issue number	3
DOIs	https://doi.org/10.1038/s41590-018-0295-8
State	Published - Mar 1 2019

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/s41590-018-0295-8

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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., ... Hambleton, S. (2019). An essential role for the Zn ²⁺ transporter ZIP7 in B cell development Nature immunology, 20(3), 350-361. https://doi.org/10.1038/s41590-018-0295-8

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, JL, Cornall, RJ, Conley, ME & Hambleton, S 2019, ' An essential role for the Zn ²⁺ transporter ZIP7 in B cell development ', Nature immunology, vol. 20, no. 3, pp. 350-361. https://doi.org/10.1038/s41590-018-0295-8

@article{8b50df72086a4b698f54024a9d956a99,

title = " An essential role for the Zn 2+ transporter ZIP7 in B cell development ",

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 Zn 2+ in modulating B cell receptor signal strength and positive selection.",

author = "Consuelo Anzilotti and Swan, {David J.} and Bertrand Boisson and Mukta Deobagkar-Lele and Catarina Oliveira and Pauline Chabosseau and Engelhardt, {Karin R.} and Xijin Xu and Rui Chen and Luis Alvarez and Rolando Berlinguer-Palmini and Bull, {Katherine R.} and Eleanor Cawthorne and Cribbs, {Adam P.} and Crockford, {Tanya L.} and Dang, {Tarana Singh} and Amy Fearn and Fenech, {Emma J.} and {de Jong}, {Sarah J.} and Lagerholm, {B. Christoffer} and Ma, {Cindy S.} and David Sims and {van den Berg}, Bert and Yaobo Xu and Cant, {Andrew J.} and Gary Kleiner and Leahy, {T. Ronan} and {de la Morena}, {M. Teresa} and Puck, {Jennifer M.} and Shapiro, {Ralph S.} and {van der Burg}, Mirjam and Chapman, {J. Ross} and Christianson, {John C.} and Benjamin Davies and McGrath, {John A.} and Stefan Przyborski and {Santibanez Koref}, Mauro and Tangye, {Stuart G.} and Andreas Werner and Rutter, {Guy A.} and Sergi Padilla-Parra and Casanova, {Jean Laurent} and Cornall, {Richard J.} and Conley, {Mary Ellen} and Sophie Hambleton",

note = "Funding Information: We thank colleagues in the Newcastle University Flow Cytometry and Bioimaging Facilities for assistance. We acknowledge N. Ashley, A. Mead, P. Sopp and C. Waugh for assistance with single cell experiments and flow cytometry, D. Biggs and C. Preece for generation of the mouse models and staff at the Oxford Functional Genomics Facility for animal care. We also thank the National Diagnostic Epidermolysis Bullosa Laboratory (St Thomas{\textquoteright} Hospital, London) and the NIHR Newcastle Biomedical Research Centre. We thank K. Taylor for helpful discussions. This work was supported by the Medical Research Council (MR/J0003042/1, MR/N00275X/1 and MR/L020149/1: DIVA) (C.A., R.J.C., E.F., J.C.C. and G.A.R.); the Sir Jules Thorn Trust (12/JTA) (S.H., D.S., T.S.D. and K.E.); the St Giles Foundation, the Rockefeller University, INSERM, Paris Descartes University, Howard Hughes Medical Institute, National Institutes of Health (5P01AI061093 and 5R01AI104857) and the French National Research Agency (ANR 14-CE15-0009-01) (B.B., S.J.d.J., J.-L.C. and M.E.C.); the Wellcome Trust (WT098424AIA; 090532/Z/09/Z and 207556/Z/17/Z) (P.C., G.A.R., J.R.C., S.P.-P., B.D. and S.H.); Cancer Research UK (C52690/A19270) (C.O. and J.R.C.); Diabetes UK (BDA11/0004210 and BDA/15/0005275) (P.C., G.A.R.); the Northern Counties Kidney Research Fund (14.06) (A.F. and A.W.); the National Health and Medical Research Council of Australia (C.S.M., S.G.T.) and the Ludwig Institute for Cancer Research (E.J.F. and J.C.C.). S.H. is a Wellcome Investigator and R.J.C. is a Principal Investigator of the MRC Human Immunology Unit. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = mar,

day = "1",

doi = "10.1038/s41590-018-0295-8",

language = "English (US)",

volume = "20",

pages = "350--361",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "3",

}

TY - JOUR

T1 - An essential role for the Zn 2+ transporter ZIP7 in B cell development

AU - Anzilotti, Consuelo

AU - Swan, David J.

AU - Boisson, Bertrand

AU - Deobagkar-Lele, Mukta

AU - Oliveira, Catarina

AU - Chabosseau, Pauline

AU - Engelhardt, Karin R.

AU - Xu, Xijin

AU - Chen, Rui

AU - Alvarez, Luis

AU - Berlinguer-Palmini, Rolando

AU - Bull, Katherine R.

AU - Cawthorne, Eleanor

AU - Cribbs, Adam P.

AU - Crockford, Tanya L.

AU - Dang, Tarana Singh

AU - Fearn, Amy

AU - Fenech, Emma J.

AU - de Jong, Sarah J.

AU - Lagerholm, B. Christoffer

AU - Ma, Cindy S.

AU - Sims, David

AU - van den Berg, Bert

AU - Xu, Yaobo

AU - Cant, Andrew J.

AU - Kleiner, Gary

AU - Leahy, T. Ronan

AU - de la Morena, M. Teresa

AU - Puck, Jennifer M.

AU - Shapiro, Ralph S.

AU - van der Burg, Mirjam

AU - Chapman, J. Ross

AU - Christianson, John C.

AU - Davies, Benjamin

AU - McGrath, John A.

AU - Przyborski, Stefan

AU - Santibanez Koref, Mauro

AU - Tangye, Stuart G.

AU - Werner, Andreas

AU - Rutter, Guy A.

AU - Padilla-Parra, Sergi

AU - Casanova, Jean Laurent

AU - Cornall, Richard J.

AU - Conley, Mary Ellen

AU - Hambleton, Sophie

N1 - Funding Information: We thank colleagues in the Newcastle University Flow Cytometry and Bioimaging Facilities for assistance. We acknowledge N. Ashley, A. Mead, P. Sopp and C. Waugh for assistance with single cell experiments and flow cytometry, D. Biggs and C. Preece for generation of the mouse models and staff at the Oxford Functional Genomics Facility for animal care. We also thank the National Diagnostic Epidermolysis Bullosa Laboratory (St Thomas’ Hospital, London) and the NIHR Newcastle Biomedical Research Centre. We thank K. Taylor for helpful discussions. This work was supported by the Medical Research Council (MR/J0003042/1, MR/N00275X/1 and MR/L020149/1: DIVA) (C.A., R.J.C., E.F., J.C.C. and G.A.R.); the Sir Jules Thorn Trust (12/JTA) (S.H., D.S., T.S.D. and K.E.); the St Giles Foundation, the Rockefeller University, INSERM, Paris Descartes University, Howard Hughes Medical Institute, National Institutes of Health (5P01AI061093 and 5R01AI104857) and the French National Research Agency (ANR 14-CE15-0009-01) (B.B., S.J.d.J., J.-L.C. and M.E.C.); the Wellcome Trust (WT098424AIA; 090532/Z/09/Z and 207556/Z/17/Z) (P.C., G.A.R., J.R.C., S.P.-P., B.D. and S.H.); Cancer Research UK (C52690/A19270) (C.O. and J.R.C.); Diabetes UK (BDA11/0004210 and BDA/15/0005275) (P.C., G.A.R.); the Northern Counties Kidney Research Fund (14.06) (A.F. and A.W.); the National Health and Medical Research Council of Australia (C.S.M., S.G.T.) and the Ludwig Institute for Cancer Research (E.J.F. and J.C.C.). S.H. is a Wellcome Investigator and R.J.C. is a Principal Investigator of the MRC Human Immunology Unit. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41590-018-0295-8

DO - 10.1038/s41590-018-0295-8

M3 - Article

C2 - 30718914

AN - SCOPUS:85061203395

SN - 1529-2908

VL - 20

SP - 350

EP - 361

JO - Nature Immunology

JF - Nature Immunology

IS - 3

ER -

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

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