TY - JOUR AU - Ogunjimi, Benson AU - Zhang, Shen-Ying AU - Sørensen, Katrine B. AU - Skipper, Kristian A. AU - Carter-Timofte, Madalina AU - Kerner, Gaspard AU - Luecke, Stefanie AU - Prabakaran, Thaneas AU - Cai, Yujia AU - Meester, Josephina AU - Bartholomeus, Esther AU - Bolar, Nikhita Ajit AU - Vandeweyer, Geert AU - Claes, Charlotte AU - Sillis, Yasmine AU - Lorenzo, Lazaro AU - Fiorenza, Raffaele A. AU - Boucherit, Soraya AU - Dielman, Charlotte AU - Heynderickx, Steven AU - Elias, George AU - Kurotova, Andrea AU - Auwera, Ann Vander AU - Verstraete, Lieve AU - Lagae, Lieven AU - Verhelst, Helene AU - Jansen, Anna AU - Ramet, Jose AU - Suls, Arvid AU - Smits, Evelien AU - Ceulemans, Berten AU - Van Laer, Lut AU - Plat Wilson, Genevieve AU - Kreth, Jonas AU - Picard, Capucine AU - Von Bernuth, Horst AU - Fluss, Joël AU - Chabrier, Stephane AU - Abel, Laurent AU - Mortier, Geert AU - Fribourg, Sebastien AU - Mikkelsen, Jacob Giehm AU - Casanova, Jean-Laurent AU - Paludan, Søren R. AU - Mogensen, Trine H. T1 - Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections PY - 2017/09/01/ AB - Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI92280 VL - 127 IS - 9 UR - https://doi.org/10.1172/JCI92280 SP - 3543 EP - 3556 PB - The American Society for Clinical Investigation ER -