2. Academic Validation
  3. An essential role for the Zn2+ transporter ZIP7 in B cell development

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

  • Nat Immunol. 2019 Mar;20(3):350-361. doi: 10.1038/s41590-018-0295-8.
Consuelo Anzilotti 1,  David J Swan 2,  Bertrand Boisson 3 4 5,  Mukta Deobagkar-Lele 1,  Catarina Oliveira 6,  Pauline Chabosseau 7,  Karin R Engelhardt 2,  Xijin Xu 1,  Rui Chen 2,  Luis Alvarez 6,  Rolando Berlinguer-Palmini 8,  Katherine R Bull 1,  Eleanor Cawthorne 1,  Adam P Cribbs 9,  Tanya L Crockford 1,  Tarana Singh Dang 2,  Amy Fearn 10,  Emma J Fenech 11,  Sarah J de Jong 3,  B Christoffer Lagerholm 1,  Cindy S Ma 12 13,  David Sims 9,  Bert van den Berg 10,  Yaobo Xu 14,  Andrew J Cant 15,  Gary Kleiner 16,  T Ronan Leahy 17,  M Teresa de la Morena 18,  Jennifer M Puck 19 20,  Ralph S Shapiro 21,  Mirjam van der Burg 22,  J Ross Chapman 6,  John C Christianson 11,  Benjamin Davies 6,  John A McGrath 23,  Stefan Przyborski 24,  Mauro Santibanez Koref 14,  Stuart G Tangye 12 13,  Andreas Werner 10,  Guy A Rutter 7,  Sergi Padilla-Parra 6 25 26,  Jean-Laurent Casanova 3 4 5 27 28,  Richard J Cornall 29,  Mary Ellen Conley 30,  Sophie Hambleton 31 32
Affiliations

Affiliations

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

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