1. Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
- Author
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Broderick, Lori, Yost, Shawn, Li, Dong, McGeough, Matthew D, Booshehri, Laela M, Guaderrama, Marisela, Brydges, Susannah D, Kucharova, Karolina, Patel, Niraj C, Harr, Margaret, Hakonarson, Hakon, Zackai, Elaine, Cowell, Ian G, Austin, Caroline A, Hügle, Boris, Gebauer, Corinna, Zhang, Jianguo, Xu, Xun, Wang, Jian, Croker, Ben A, Frazer, Kelly A, Putnam, Christopher D, and Hoffman, Hal M
- Subjects
B-Lymphocytes ,Animals ,Mice ,Knockout ,Humans ,Mice ,Saccharomyces cerevisiae ,DNA Topoisomerases ,Type II ,Cell Differentiation ,Mutation ,Female ,Male ,Primary Immunodeficiency Diseases - 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.
- Published
- 2019