Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

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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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Figure 1: Schematic of AGS2 critical region and RNASEH2B gene depicting location of identified mutations.
Figure 2: Schematic of AGS3 region, the RNASEH2C gene, its mutations and sequence conservation in other species.
Figure 3: The RNASEH2A gene, genomic location, gene structure and mutation location.
Figure 4: Human RNASEH2B, RNASEH2C and RNASEH2A form an enzymatically active type II ribonuclease H complex when expressed in mammalian cells, and mutation in RNASEH2A reduces ribonuclease H activity.

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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.

Author information

Y.J.C. and R.P. performed the microsatellite genotyping; A.P.J. performed linkage analysis and A.G., A.L., B.H., R.P. and A.P.J performed mutation screening and sequencing of controls. A.L. and A.P.J. made the vector constructs and designed the enzyme assays. A.L. and E.G. performed the immunoprecipitations and enzyme assays. C.P.P. established orthology between RNASEH2B and Rnh2Bp and between RNASEH2C and Rnh2Cp, and C.S. performed the structural modeling. A.P.J. wrote the paper with Y.J.C., D.T.B. and C.P.P. Y.J.C. curated the clinical samples and data. All other authors provided clinical samples and data.

Note: Supplementary information is available on the Nature Genetics website..

Correspondence to Yanick J Crow or Andrew P Jackson.

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Competing interests

On behalf of the authors, Medical Research Council Technology has filed a patent application for the human ribonuclease H2 complex.

Supplementary information

Supplementary Fig. 1

Neuroimaging and clinical findings in Aicardi-Goutières syndrome. (PDF 459 kb)

Supplementary Fig. 2

Microsatellite genotyping in two non-consanguineous families refines the AGS2 critical interval. (PDF 33 kb)

Supplementary Fig. 3

Multiple sequence alignment of RNASEH2B/Rnh2Bp and RNASEH2C/Rnh2Cp homologs from representative eukaryotic species. (PDF 56 kb)

Supplementary Fig. 4

The AGS3 locus maps to chromosome 11q13.2. (PDF 36 kb)

Supplementary Fig. 5

Pedigrees of families described. (PDF 50 kb)

Supplementary Table 1

Primer sequences (PDF 30 kb)

Supplementary Note (PDF 17 kb)

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