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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Aicardi, J. & Goutières, F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann. Neurol. 15, 49–54 (1984).
Goutières, F. Aicardi-Goutières syndrome. Brain Dev. 27, 201–206 (2005).
Goutières, F., Aicardi, J., Barth, P.G. & Lebon, P. Aicardi-Goutières syndrome: an update and results of interferon-alpha studies. Ann. Neurol. 44, 900–907 (1998).
Bale, J.F., Jr ., Bray, P.F. & Bell, W.E. Neuroradiographic abnormalities in congenital cytomegalovirus infection. Pediatr. Neurol. 1, 42–47 (1985).
Numazaki, K. & Fujikawa, T. Intracranial calcification with congenital rubella syndrome in a mother with serologic immunity. J. Child Neurol. 18, 296–297 (2003).
Mitchell, W. Neurological and developmental effects of HIV and AIDS in children and adolescents. Ment. Retard. Dev. Disabil. Res. Rev. 7, 211–216 (2001).
Belman, A.L. et al. AIDS: calcification of the basal ganglia in infants and children. Neurology 36, 1192–1199 (1986).
Lebon, P., Meritet, J.F., Krivine, A. & Rozenberg, F. Interferon and Aicardi-Goutières syndrome. Eur. J. Paediatr. Neurol. 6 (Suppl.), A47–A53 (2002).
Krivine, A. et al. Measuring HIV-1 RNA and interferon-alpha in the cerebrospinal fluid of AIDS patients: insights into the pathogenesis of AIDS Dementia Complex. J. Neurovirol. 5, 500–506 (1999).
Lebon, P., Ponsot, G., Aicardi, J., Goutières, F. & Arthuis, M. Early intrathecal synthesis of interferon in herpes encephalitis. Biomedicine 31, 267–271 (1979).
Dussaix, E., Lebon, P., Ponsot, G., Huault, G. & Tardieu, M. Intrathecal synthesis of different alpha-interferons in patients with various neurological diseases. Acta Neurol. Scand. 71, 504–509 (1985).
Kumar, D., Rittey, C., Cameron, A.H. & Variend, S. Recognizable inherited syndrome of progressive central nervous system degeneration and generalized intracranial calcification with overlapping phenotype of the syndrome of Aicardi and Goutières. Am. J. Med. Genet. 75, 508–515 (1998).
Crow, Y.J. et al. Aicardi-Goutières syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21. Am. J. Hum. Genet. 67, 213–221 (2000).
Crow, Y.J. et al. Cree encephalitis is allelic with Aicardi-Goutières syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism. J. Med. Genet. 40, 183–187 (2003).
Ali, M. et al. A second locus for Aicardi-Goutières syndrome at chromosome 13q14–21. J. Med. Genet. 43, 444–450 (2006).
Broman, K.W. & Weber, J.L. Long homozygous chromosomal segments in reference families from the Centre d'Etude du Polymorphisme Humain. Am. J. Hum. Genet. 65, 1493–1500 (1999).
Gibson, J., Morton, N.E. & Collins, A. Extended tracts of homozygosity in outbred human populations. Hum. Mol. Genet. 15, 789–795 (2006).
Lander, E.S. & Botstein, D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 236, 1567–1570 (1987).
Henikoff, S. & Henikoff, J.G. Amino acid substitution matrices from protein blocks. Proc. Natl. Acad. Sci. USA 89, 10915–10919 (1992).
Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).
Jeong, H.S., Backlund, P.S., Chen, H.C., Karavanov, A.A. & Crouch, R.J. RNase H2 of Saccharomyces cerevisiae is a complex of three proteins. Nucleic Acids Res. 32, 407–414 (2004).
Ohtani, N. et al. Identification of the genes encoding Mn2+-dependent RNase HII and Mg2+-dependent RNase HIII from Bacillus subtilis: classification of RNases H into three families. Biochemistry 38, 605–618 (1999).
Frank, P., Braunshofer-Reiter, C., Wintersberger, U., Grimm, R. & Busen, W. Cloning of the cDNA encoding the large subunit of human RNase HI, a homologue of the prokaryotic RNase HII. Proc. Natl. Acad. Sci. USA 95, 12872–12877 (1998).
Arudchandran, A. et al. The absence of ribonuclease H1 or H2 alters the sensitivity of Saccharomyces cerevisiae to hydroxyurea, caffeine and ethyl methanesulphonate: implications for roles of RNases H in DNA replication and repair. Genes Cells 5, 789–802 (2000).
Eder, P.S. & Walder, J.A. Ribonuclease H from K562 human erythroleukemia cells. Purification, characterization, and substrate specificity. J. Biol. Chem. 266, 6472–6479 (1991).
Qiu, J., Qian, Y., Frank, P., Wintersberger, U. & Shen, B. Saccharomyces cerevisiae RNase H(35) functions in RNA primer removal during lagging-strand DNA synthesis, most efficiently in cooperation with Rad27 nuclease. Mol. Cell. Biol. 19, 8361–8371 (1999).
Eder, P.S., Walder, R.Y. & Walder, J.A. Substrate specificity of human RNase H1 and its role in excision repair of ribose residues misincorporated in DNA. Biochimie 75, 123–126 (1993).
Rydberg, B. & Game, J. Excision of misincorporated ribonucleotides in DNA by RNase H (type 2) and FEN-1 in cell-free extracts. Proc. Natl. Acad. Sci. USA 99, 16654–16659 (2002).
Sanchis, A. et al. Genetic syndromes mimic congenital infections. J. Pediatr. 146, 701–705 (2005).
Chapados, B.R. et al. Structural biochemistry of a type 2 RNase H: RNA primer recognition and removal during DNA replication. J. Mol. Biol. 307, 541–556 (2001).
Parniak, M.A., Min, K.L., Budihas, S.R., Le Grice, S.F. & Beutler, J.A. A fluorescence-based high-throughput screening assay for inhibitors of human immunodeficiency virus-1 reverse transcriptase-associated ribonuclease H activity. Anal. Biochem. 322, 33–39 (2003).
Baraitser, M., Brett, E.M. & Piesowicz, A.T. Microcephaly and intracranial calcification in two brothers. J. Med. Genet. 20, 210–212 (1983).
Reardon, W. et al. Autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease. Am. J. Med. Genet. 52, 58–65 (1994).
Schwarz, K.B., Ferrie, C.D. & Woods, C.G. Two siblings with a new Aicardi-Goutières-like syndrome. Dev. Med. Child Neurol. 44, 422–425 (2002).
Gardner, R.J. et al. Severe fetal brain dysgenesis with focal calcification. Prenat. Diagn. 25, 362–364 (2005).
Coffin, J.M., Hughes, S.H. & Varmus, H.E. Retroviruses (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1997).
Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nat. Immunol. 7, 131–137 (2006).
Campbell, I.L. et al. Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha. Brain Res. 835, 46–61 (1999).
Jackson, A.P. et al. Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am. J. Hum. Genet. 63, 541–546 (1998).
Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis: A unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996).
Goodstadt, L. & Ponting, C.P. CHROMA: consensus-based colouring of multiple alignments for publication. Bioinformatics 17, 845–846 (2001).
Schwede, T., Kopp, J., Guex, N. & Peitsch, M.C. SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res. 31, 3381–3385 (2003).
Hooft, R.W., Vriend, G., Sander, C. & Abola, E.E. Errors in protein structures. Nature 381, 272 (1996).
Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 33-38–27-28 (1996).
Van Aelst, L., Joneson, T. & Bar-Sagi, D. Identification of a novel Rac1-interacting protein involved in membrane ruffling. EMBO J. 15, 3778–3786 (1996).
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.
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)
About this article
Genes and Environment (2019)
Nature Neuroscience (2019)
Current Genetics (2019)
Scientific Reports (2018)