Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Benson Ogunjimi, Shen-Ying Zhang, Katrine B. Sorensen, Kristian A. Skipper, Madalina Carter-Timofte, Gaspard Kerner, Stefanie Luecke, Thaneas Prabakaran, Yujia Cai, Josephina Meester, Esther Bartholomeus, Nikhita Ajit Bolar, Geert Vandeweyer, Charlotte Claes, Yasmine Sillis, Lazaro Lorenzo, Raffaele A. Fiorenza, Soraya Boucherit, Charlotte Dielman, Steven HeynderickxGeorge Elias, Andrea Kurotova, Ann Vander Auwera, Lieve Verstraete, Lieven Lagae, Helene Verhelst, Anna Jansen, Jose Ramet, Arvid Suls, Evelien Smits, Berten Ceulemans, Lut Van Laer, Genevieve Plat Wilson, Jonas Kreth, Capucine Picard, Horst Von Bernuth, Joel Fluss, Stephane Chabrier, Laurent Abel, Geert Mortier, Sebastien Fribourg, Jacob Giehm Mikkelsen, Jean-Laurent Casanova, Soren R. Paludan, Trine H. Mogensen

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)


Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to lifethreatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.

Original languageEnglish
Pages (from-to)3543-3556
Number of pages14
JournalJournal of Clinical Investigation
Issue number9
Publication statusPublished - 1 Sep 2017


  • Alleles
  • Animals
  • Chickenpox/genetics
  • Child
  • DNA Mutational Analysis
  • Gene Expression Regulation, Enzymologic
  • HEK293 Cells
  • Herpes Zoster/genetics
  • Herpesvirus 3, Human
  • Heterozygote
  • Humans
  • Leukocytes/metabolism
  • Mice
  • Mutation
  • Mutation, Missense
  • Phenotype
  • RNA Polymerase III/genetics


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