Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.
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We thank the families and their clinicians for their participation in this study; G. Taylor, S. Farrington and C. Hayward for contributing control samples; A. Diamond for advice on Mutation Surveyor; S. McKay and the MRC HGU core sequencing service for advice and technical support; D. Stuart for preparation of illustrations; P. Hohenstein and N. Gilbert for assistance with reagents; V. Van Heyningen, J. Sanford, D. Fitzpatrick, W. Bickmore, B. Vernay, A. Wright and N. Hastie for discussions and comments; F.B. Longo and the International Aicardi-Goutières syndrome Association for their encouragement and K. Norton, L. Cervero and G. Pitelet for their help clinically. This work was supported by the MRC, the Fondazione Cariplo, The Leeds Teaching Hospitals Charitable Foundation and the West Riding Medical Research Trust. A.P.J. is an MRC Clinician Scientist, and A.P.J. and CPP are funded by the MRC.
On behalf of the authors, Medical Research Council Technology has filed a patent application for the human ribonuclease H2 complex.
Neuroimaging and clinical findings in Aicardi-Goutières syndrome. (PDF 459 kb)
Microsatellite genotyping in two non-consanguineous families refines the AGS2 critical interval. (PDF 33 kb)
Multiple sequence alignment of RNASEH2B/Rnh2Bp and RNASEH2C/Rnh2Cp homologs from representative eukaryotic species. (PDF 56 kb)
The AGS3 locus maps to chromosome 11q13.2. (PDF 36 kb)
Pedigrees of families described. (PDF 50 kb)
Primer sequences (PDF 30 kb)
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Frontiers in Microbiology (2019)
Frontiers in Immunology (2019)
Current Genetics (2019)