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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Cell Differentiation
  • DNA Topoisomerases, Type II / genetics*
  • DNA Topoisomerases, Type II / immunology
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Primary Immunodeficiency Diseases / enzymology*
  • Primary Immunodeficiency Diseases / genetics
  • Primary Immunodeficiency Diseases / immunology
  • Primary Immunodeficiency Diseases / physiopathology
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics


  • DNA Topoisomerases, Type II