Mutations in topoisomerase IIβ result in a B cell immunodeficiency

Nat Commun. 2019 Aug 13;10(1):3644. doi: 10.1038/s41467-019-11570-6.

Lori Broderick ¹ ², Shawn Yost ³ ⁴, Dong Li ⁵, Matthew D McGeough ³ ⁶, Laela M Booshehri ³, Marisela Guaderrama ³, Susannah D Brydges ⁷, Karolina Kucharova ⁸, Niraj C Patel ⁹, Margaret Harr ¹⁰ ¹¹, Hakon Hakonarson ⁵ ¹¹, Elaine Zackai ¹⁰ ¹¹, Ian G Cowell ¹², Caroline A Austin ¹², Boris Hügle ¹³, Corinna Gebauer ¹⁴, Jianguo Zhang ¹⁵ ¹⁶, Xun Xu ¹⁵ ¹⁶, Jian Wang ¹⁵ ¹⁶, Ben A Croker ³, Kelly A Frazer ³ ¹⁷ ¹⁸, Christopher D Putnam ⁶ ¹⁹, Hal M Hoffman ³ ¹⁷ ⁶

Affiliations

1 Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA. lbroderick@ucsd.edu.
2 Rady Children's Hospital of San Diego, San Diego, CA, 92123, USA. lbroderick@ucsd.edu.
3 Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA.
4 Division of Genetics and Epidemiology, Institute of Cancer Research, London, SM2 5NG, UK.
5 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
6 Department of Medicine, University of California at San Diego, La Jolla, CA, 92093, USA.
7 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA.
8 Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92093, USA.
9 Department of Pediatrics, Levine Children's Hospital, Atrium Health, Charlotte, NC, 28203, USA.
10 Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
11 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
12 Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
13 German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, 82467, Germany.
14 Division of Neonatology, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, 04109, Germany.
15 BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, 518083, China.
16 China National GeneBank, BGI-Shenzhen, Jinsha Road, Shenzhen, 518120, China.
17 Rady Children's Hospital of San Diego, San Diego, CA, 92123, USA.
18 Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
19 San Diego Branch, Ludwig Institute of Cancer Research, La Jolla, CA, 92093, USA.

PMID: 31409799 DOI: 10.1038/s41467-019-11570-6

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.

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