Mutations in topoisomerase IIβ result in a B cell immunodeficiency.

Autor: Broderick L; Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA. lbroderick@ucsd.edu.; Rady Children's Hospital of San Diego, San Diego, CA, 92123, USA. lbroderick@ucsd.edu., Yost S; Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA.; Division of Genetics and Epidemiology, Institute of Cancer Research, London, SM2 5NG, UK., Li D; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., McGeough MD; Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA.; Department of Medicine, University of California at San Diego, La Jolla, CA, 92093, USA., Booshehri LM; Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA., Guaderrama M; Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA., Brydges SD; Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA., Kucharova K; Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92093, USA., Patel NC; Department of Pediatrics, Levine Children's Hospital, Atrium Health, Charlotte, NC, 28203, USA., Harr M; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA., Hakonarson H; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA., Zackai E; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA., Cowell IG; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Austin CA; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Hügle B; German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, 82467, Germany., Gebauer C; Division of Neonatology, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, 04109, Germany., Zhang J; BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, 518083, China.; China National GeneBank, BGI-Shenzhen, Jinsha Road, Shenzhen, 518120, China., Xu X; BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, 518083, China.; China National GeneBank, BGI-Shenzhen, Jinsha Road, Shenzhen, 518120, China., Wang J; BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, 518083, China.; China National GeneBank, BGI-Shenzhen, Jinsha Road, Shenzhen, 518120, China., Croker BA; Department of Pediatrics, University of California at San Diego, La Jolla, CA, 92093, USA., Frazer KA; 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.; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Putnam CD; Department of Medicine, University of California at San Diego, La Jolla, CA, 92093, USA.; San Diego Branch, Ludwig Institute of Cancer Research, La Jolla, CA, 92093, USA., Hoffman HM; 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.; Department of Medicine, University of California at San Diego, La Jolla, CA, 92093, USA.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Aug 13; Vol. 10 (1), pp. 3644. Date of Electronic Publication: 2019 Aug 13.
DOI: 10.1038/s41467-019-11570-6
Abstrakt: 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.
Databáze: MEDLINE