Abstract
Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2−/− mice using CRISPR/Cas9-mediated genome editing. Rnaset2−/− mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8+ effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2−/− mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies.
Highlights
Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment
Founder lines were screened for an early stop codon at the end of exon 2 in the Rnaset2b locus and for the transgenic cassette (EUCOMM) in the Rnaset2a gene by PCR and Sanger sequencing (Supplementary Fig. 1a)
Expression changes were evident for a cluster that we identified as microglia/monocytes and for astrocytes, oligodendrocytes, oligodendrocyte precursor cells (OPC), and three clusters representing neurons
Summary
Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. Rnaset2−/− mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1dependent neuroinflammation, with infiltration of CD8+ effector memory T cells and inflammatory monocytes into the grey and white matter. The Rnaset2−/− mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies. Brain magnetic resonance imaging (MRI) reveals frontal and temporal lobe cystic lesions, multifocal white matter alterations, and cerebral atrophy[1,2]. There is a significant clinical and neuroradiological overlap of RNaseT2-deficient CLE with Aicardi-Goutières syndrome (AGS), with some affected individuals demonstrating cerebrospinal fluid (CSF) pleocytosis, elevated levels of CSF neopterin as an inflammatory marker, and an overexpression of interferon-stimulated genes (ISGs) in peripheral blood[3]. IFN-I in the CSF is a hallmark of AGS and considered the principle driver of the severe autoinflammatory encephalopathy observed in these patients
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