Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA.
Rady Children's Hospital of San Diego, San Diego, CA, 92123, USA.
Nat Commun. 2019 Aug 13;10(1):3644. doi: 10.1038/s41467-019-11570-6.
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.
B 细胞发育是一个高度调控的过程，涉及多个分化步骤，但该途径的许多细节仍不清楚。对 B 细胞受限免疫缺陷患者的测序揭示了 TOP2B 中的常染色体显性突变。TOP2B 编码一种 II 型拓扑异构酶，这是一种在 DNA 复制和基因转录过程中缓解拓扑应力所必需的必需基因，以前在 B 细胞发育中没有已知的作用。我们使用酿酒酵母、基因敲入和基因敲除的小鼠模型，证明 TOP2B 中的患者突变对酶功能具有显性负效应，导致 B-2 细胞增殖和存活受损，从而导致 B 细胞发育受阻，并损害对免疫接种的体液功能。
