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Nat Immunol. 2019 Feb 4. doi: 10.1038/s41590-018-0295-8. [Epub ahead of print]

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

Author information

1
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
2
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
3
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
4
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163 Necker Hospital for Sick Children, Paris, France.
5
Paris Descartes University, Imagine Institute, Paris, France.
6
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
7
Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College, London, UK.
8
Bioimaging Unit, Newcastle University Medical School, Newcastle upon Tyne, UK.
9
MRC WIMM Centre for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
10
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK.
11
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
12
Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
13
St Vincent's Clinical School, Faculty of Medicine, University of NSW, Darlinghurst, New South Wales, Australia.
14
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
15
Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
16
Pediatric Allergy and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.
17
Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
18
Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.
19
Department of Pediatrics, Division of Allergy, Immunology, and Blood and Bone Marrow Transplantation, University of California, San Francisco, CA, USA.
20
UCSF Benioff Children's Hospital, San Francisco, CA, USA.
21
Midwest Immunology Clinic, Plymouth, MN, USA.
22
Department of Immunology, Erasmus University Medical Centre, Rotterdam, the Netherlands.
23
St John's Institute of Dermatology, King's College London, London, UK.
24
Department of Biosciences, Durham University, Durham, UK.
25
Dynamic Structural Virology Group, Biocruces Health Research Institute, Barakaldo, Spain.
26
Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
27
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
28
Howard Hughes Medical Institute, New York, NY, USA.
29
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. richard.cornall@ndm.ox.ac.uk.
30
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. conley.maryellen@gmail.com.
31
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. sophie.hambleton@newcastle.ac.uk.
32
Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. sophie.hambleton@newcastle.ac.uk.

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.

PMID:
30718914
DOI:
10.1038/s41590-018-0295-8

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