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Mutations in topoisomerase IIβ result in a B cell immunodeficiency

Author

Listed:
  • Lori Broderick

    (University of California at San Diego
    Rady Children’s Hospital of San Diego)

  • Shawn Yost

    (University of California at San Diego
    Institute of Cancer Research)

  • Dong Li

    (Children’s Hospital of Philadelphia)

  • Matthew D. McGeough

    (University of California at San Diego
    University of California at San Diego)

  • Laela M. Booshehri

    (University of California at San Diego)

  • Marisela Guaderrama

    (University of California at San Diego)

  • Susannah D. Brydges

    (Regeneron Pharmaceuticals, Inc.)

  • Karolina Kucharova

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Niraj C. Patel

    (Levine Children’s Hospital, Atrium Health)

  • Margaret Harr

    (Children’s Hospital of Philadelphia
    University of Pennsylvania School of Medicine)

  • Hakon Hakonarson

    (Children’s Hospital of Philadelphia
    University of Pennsylvania School of Medicine)

  • Elaine Zackai

    (Children’s Hospital of Philadelphia
    University of Pennsylvania School of Medicine)

  • Ian G. Cowell

    (Newcastle University)

  • Caroline A. Austin

    (Newcastle University)

  • Boris Hügle

    (German Center for Pediatric and Adolescent Rheumatology)

  • Corinna Gebauer

    (University Hospital for Children and Adolescents, University of Leipzig)

  • Jianguo Zhang

    (BGI-Shenzhen, Beishan Industrial Zone
    China National GeneBank, BGI-Shenzhen)

  • Xun Xu

    (BGI-Shenzhen, Beishan Industrial Zone
    China National GeneBank, BGI-Shenzhen)

  • Jian Wang

    (BGI-Shenzhen, Beishan Industrial Zone
    China National GeneBank, BGI-Shenzhen)

  • Ben A. Croker

    (University of California at San Diego)

  • Kelly A. Frazer

    (University of California at San Diego
    Rady Children’s Hospital of San Diego
    University of California San Diego)

  • Christopher D. Putnam

    (University of California at San Diego
    Ludwig Institute of Cancer Research)

  • Hal M. Hoffman

    (University of California at San Diego
    Rady Children’s Hospital of San Diego
    University of California at San Diego)

Abstract

B cell development is a highly regulated process involving multiple differentiation steps, yet many details regarding this pathway remain unknown. Sequencing of patients with B cell-restricted immunodeficiency reveals autosomal dominant mutations in TOP2B. TOP2B encodes a type II topoisomerase, an essential gene required to alleviate topological stress during DNA replication and gene transcription, with no previously known role in B cell development. We use Saccharomyces cerevisiae, and knockin and knockout murine models, to demonstrate that patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization.

Suggested Citation

  • Lori Broderick & Shawn Yost & Dong Li & Matthew D. McGeough & Laela M. Booshehri & Marisela Guaderrama & Susannah D. Brydges & Karolina Kucharova & Niraj C. Patel & Margaret Harr & Hakon Hakonarson & , 2019. "Mutations in topoisomerase IIβ result in a B cell immunodeficiency," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11570-6
    DOI: 10.1038/s41467-019-11570-6
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