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

C Anzilotti; David J. Swan; Bertrand Boisson; Mukta Deobagkar-Lele; C Oliveira; Pauline Chabosseau; Karin R. Engelhardt; X Xu; R Chen; L Alvarez; Rolando Berlinguer-Palmini; Katherine R. Bull; Eleanor Cawthorne; Adam P. Cribbs; AP Crockford; Tarana Singh Dang; Amy Fearn; Emma J. Fenech; S. de Jong; B. Christoffer Lagerholm; C Ma; David Sims; Bert van den Berg; Y Xu; Andrew J. Cant; Gary Kleiner; T. Ronan Leahy; John Alexander McGrath; Stefan Przyborski; Mauro Santibanez-Koref; Stuart G Tangye; Andreas Werner; Guy A. Rutter; Sergi Padilla Parra; J Casanova; Richard Cornall; Mary Ellen Conley; Sophie Hambleton

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

C Anzilotti, David J. Swan, Bertrand Boisson, Mukta Deobagkar-Lele, C Oliveira, Pauline Chabosseau, Karin R. Engelhardt, X Xu, R Chen, L Alvarez, Rolando Berlinguer-Palmini, Katherine R. Bull, Eleanor Cawthorne, Adam P. Cribbs, AP Crockford, Tarana Singh Dang, Amy Fearn, Emma J. Fenech, S. de Jong, B. Christoffer LagerholmC Ma, David Sims, Bert van den Berg, Y Xu, Andrew J. Cant, Gary Kleiner, T. Ronan Leahy, John Alexander McGrath, Stefan Przyborski, Mauro Santibanez-Koref, Stuart G Tangye, Andreas Werner, Guy A. Rutter, Sergi Padilla Parra, J Casanova, Richard Cornall, Mary Ellen Conley, Sophie Hambleton

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

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.

Original language	English
Pages (from-to)	350-361
Journal	Nature Immunology
Publication status	Published - Mar 2019

Cite this

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, AP., Dang, T. S., Fearn, A., Fenech, E. J., de Jong, S., ... Hambleton, S. (2019). An essential role for the Zn2+ transporter ZIP7 in B cell development. Nature Immunology, 350-361.

@article{381521cb54b945e8883d76e1412faf69,

title = "An essential role for the Zn2+ 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 Zn2+ in modulating B cell receptor signal strength and positive selection.",

author = "C Anzilotti and Swan, {David J.} and Bertrand Boisson and Mukta Deobagkar-Lele and C Oliveira and Pauline Chabosseau and Engelhardt, {Karin R.} and X Xu and R Chen and L Alvarez and Rolando Berlinguer-Palmini and Bull, {Katherine R.} and Eleanor Cawthorne and Cribbs, {Adam P.} and AP Crockford and Dang, {Tarana Singh} and Amy Fearn and Fenech, {Emma J.} and {de Jong}, S. and Lagerholm, {B. Christoffer} and C Ma and David Sims and {van den Berg}, Bert and Y Xu and Cant, {Andrew J.} and Gary Kleiner and Leahy, {T. Ronan} and McGrath, {John Alexander} and Stefan Przyborski and Mauro Santibanez-Koref and Tangye, {Stuart G} and Andreas Werner and Rutter, {Guy A.} and {Padilla Parra}, Sergi and J Casanova and Richard Cornall and Conley, {Mary Ellen} and Sophie Hambleton",

year = "2019",

month = mar,

language = "English",

pages = "350--361",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

}

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, AP, Dang, TS, Fearn, A, Fenech, EJ, de Jong, S, Lagerholm, BC, Ma, C, Sims, D, van den Berg, B, Xu, Y, Cant, AJ, Kleiner, G, Leahy, TR, McGrath, JA, Przyborski, S, Santibanez-Koref, M, Tangye, SG, Werner, A, Rutter, GA, Padilla Parra, S, Casanova, J, Cornall, R, Conley, ME & Hambleton, S 2019, 'An essential role for the Zn2+ transporter ZIP7 in B cell development', Nature Immunology, pp. 350-361.

TY - JOUR

T1 - An essential role for the Zn2+ transporter ZIP7 in B cell development

AU - Anzilotti, C

AU - Swan, David J.

AU - Boisson, Bertrand

AU - Deobagkar-Lele, Mukta

AU - Oliveira, C

AU - Chabosseau, Pauline

AU - Engelhardt, Karin R.

AU - Xu, X

AU - Chen, R

AU - Alvarez, L

AU - Berlinguer-Palmini, Rolando

AU - Bull, Katherine R.

AU - Cawthorne, Eleanor

AU - Cribbs, Adam P.

AU - Crockford, AP

AU - Dang, Tarana Singh

AU - Fearn, Amy

AU - Fenech, Emma J.

AU - de Jong, S.

AU - Lagerholm, B. Christoffer

AU - Ma, C

AU - Sims, David

AU - van den Berg, Bert

AU - Xu, Y

AU - Cant, Andrew J.

AU - Kleiner, Gary

AU - Leahy, T. Ronan

AU - McGrath, John Alexander

AU - Przyborski, Stefan

AU - Santibanez-Koref, Mauro

AU - Tangye, Stuart G

AU - Werner, Andreas

AU - Rutter, Guy A.

AU - Padilla Parra, Sergi

AU - Casanova, J

AU - Cornall, Richard

AU - Conley, Mary Ellen

AU - Hambleton, Sophie

PY - 2019/3

Y1 - 2019/3

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 Zn2+ 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 Zn2+ in modulating B cell receptor signal strength and positive selection.

M3 - Article

SN - 1529-2908

SP - 350

EP - 361

JO - Nature Immunology

JF - Nature Immunology

ER -

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

Abstract

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