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Neurol Neuroimmunol Neuroinflamm. 2018 Sep 7;5(6):e500. doi: 10.1212/NXI.0000000000000500. eCollection 2018 Nov.

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

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Departments of Infectious Diseases (M.E.C-T., A.F.H., M.M., C.S.L., T.H.M), Clinical Immunology (M.C.), and Clinical Medicine (T.H.M), Aarhus University Hospital, Denmark; Université de Bordeaux (S.F.), INSERM U1212, CNRS 5320, France; St.Giles Laboratory of Human Genetics of Infectious Diseases (F.R., S.-Y.Z., J.-L.C.), Rockefeller Branch, the Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases (S.-Y.Z., J.-L.C.), Necker Branch, INSERM UMR 1163; Paris Descartes University (S.-Y.Z, J.-L.C.), Imagine Institute, France; and Department of Biomedicine (M.E.C-T., S.R.P., T.H.M.), Aarhus University (AU).



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.


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.


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.


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.

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