Mutations in topoisomerase IIβ result in a B cell immunodeficiency

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, Elaine Zackai, Ian G. Cowell, Caroline A. Austin, Boris Hügle, Corinna Gebauer, Jianguo Zhang, Xun Xu, Jian Wang, Ben A. Croker, Kelly A. Frazer, Christopher D. Putnam and Hal M. Hoffman
Additional contact information
Lori Broderick: University of California at San Diego
Shawn Yost: University of California at San Diego
Dong Li: Children’s Hospital of Philadelphia
Matthew D. McGeough: 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
Hakon Hakonarson: Children’s Hospital of Philadelphia
Elaine Zackai: Children’s Hospital of Philadelphia
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
Xun Xu: BGI-Shenzhen, Beishan Industrial Zone
Jian Wang: BGI-Shenzhen, Beishan Industrial Zone
Ben A. Croker: University of California at San Diego
Kelly A. Frazer: University of California at San Diego
Christopher D. Putnam: University of California at San Diego
Hal M. Hoffman: University of California at San Diego

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11570-6

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