Mutations in topoisomerase IIβ result in a B cell immunodeficiency.

Mutations in topoisomerase IIβ result in a B cell immunodeficiency.

Nature communications (2019-08-15)

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, Hal M Hoffman

PMID31409799

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.