PT - JOURNAL ARTICLE AU - Madalina E Carter-Timofte AU - Anders F Hansen AU - Maibritt Mardahl AU - Sébastien Fribourg AU - Franck Rapaport AU - Shen-Ying Zhang AU - Jean-Laurent Casanova AU - Søren R Paludan AU - Mette Christiansen AU - Carsten S Larsen AU - Trine H Mogensen TI - Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins AID - 10.1101/244848 DP - 2018 Jan 01 TA - bioRxiv PG - 244848 4099 - http://biorxiv.org/content/early/2018/01/08/244848.short 4100 - http://biorxiv.org/content/early/2018/01/08/244848.full AB - Deficiency in the cytosolic DNA sensor RNA Polymerase III was recently described in children with severe varicella zoster infection in the CNS or lungs. Here we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings included recurrent episodes of headache, dizziness, and neurological deficits, cerebrospinal fluid with pleocytosis and intrathecal VZV antibody production, and magnetic resonance scan of the brain showing ischaemic lesions. We performed whole exome sequencing and identified a rare mutation in the Pol III subunit POLR3F. The identified R50W POLR3F mutation is predicted to be damaging by bioinformatics and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the PoL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, these cases add genetic and immunological evidence to the novel association between defects in sensing of AT-rich DNA present in the VZV genome and increased susceptibility to severe manifestations of VZV infection in the CNS in humans.CADDcombined annotation dependent depletionCSFcerebrospinal fluidDOCKdedicator of cytokinesisIFNGRinterferon gamma receptorMSCmutation significance cut-offNKnatural killerPOLIIIRNA polymerase IIISCIDsevere combined immunodeficiencyTYKtyrosine kinaseVZVvaricella zoster virusWESwhole exome sequencing