학술논문
Mutations in topoisomerase IIβ result in a B cell immunodeficiency.
Document Type
article
Author
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; Hoffman, Hal M
Source
Nature communications. 10(1)
Subject
Language
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.