Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection.

Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E. In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, this study provides significant extension on the current knowledge on susceptibility to VZV infection by demonstrating mutations in POL III genes associated with impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection.

Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins.

OBJECTIVE: Deficiency in the cytosolic DNA sensor RNA Polymerase III (POL III) was recently described in children with severe varicella-zoster virus (VZV) 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 neurologic deficits, CSF with pleocytosis and intrathecal VZV antibody production, and MRI of the brain showing ischemic lesions. METHODS: We performed whole-exome sequencing and identified a rare mutation in the POL III subunit POLR3F. Subsequently, antiviral responses in patient peripheral blood mononuclear cells (PBMCs) were examined and compared with healthy controls. RESULTS: The identified R50W POLR3F mutation is predicted by bioinformatics to be damaging, and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the POL III agonist poly(dA:dT) and increased viral replication compared with controls. CONCLUSIONS: Altogether, these cases add genetic and immunologic 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.