Congenital cytomegalovirus brain infection without symptoms at birth can cause a static encephalopathy with characteristic patterns of brain abnormalities. Here we show that loss-of-function mutations in the gene encoding the RNASET2 glycoprotein lead to cystic leukoencephalopathy, an autosomal recessive disorder with an indistinguishable clinical and neuroradiological phenotype. Congenital cytomegalovirus infection and RNASET2 deficiency may both interfere with brain development and myelination through angiogenesis or RNA metabolism.

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We thank the subjects and their families for participating in the study, C. Becker, L. Florin, M. Grapp, R. Hitt, J. Landgrebe and G. Nürnberg for expert technical assistance, and A. Fuchs, T.V.O. Hansen, R. Sedlmeier, O. Shoseyov and G. Tretter for collaborative efforts. This work has been supported by the Deutsche Forschungsgemeinschaft Grant GA354/6-1 (J.G. and M.H.) and the Bundesministerium für Bildung and Forschung (BMBF) through the German Leukodystrophy Network (M.H. and J.S.).

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  1. Department of Pediatrics and Pediatric Neurology, Georg August University, Göttingen, Germany.

    • Marco Henneke
    • , Simone Diekmann
    • , Andreas Ohlenbusch
    • , Jens Kaiser
    • , Ralph Krätzner
    • , Sven Thoms
    • , Robert Steinfeld
    •  & Jutta Gärtner
  2. Institute of Diagnostic and Interventional Radiology, Hospital St. Marien, Amberg, Germany.

    • Volkher Engelbrecht
  3. Department of Pediatrics, University Medical Center, Hamburg-Eppendorf, Germany.

    • Alfried Kohlschütter
  4. Department of Neuropediatrics, University Hospital Virgen del Rocío, Sevilla, Spain.

    • Marcos Madruga-Garrido
  5. AP-HP, Department of Neuropediatrics, Armand Trousseau Hospital, Paris, France.

    • Michèle Mayer
    •  & Diana Rodriguez
  6. DNA Microarray Facility, Georg August University, Göttingen, Germany.

    • Lennart Opitz
  7. INSERM UMR S546, Paris, France.

    • Diana Rodriguez
  8. Pierre and Marie Curie University, Paris, France.

    • Diana Rodriguez
  9. Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany.

    • Franz Rüschendorf
  10. Institute of Human Genetics, University of Bonn, Germany.

    • Johannes Schumacher
  11. Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Johannes Schumacher
  12. Cologne Center for Genomics (CCG) and Institute for Genetics, University of Cologne, Germany.

    • Holger Thiele
    •  & Peter Nürnberg
  13. Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Germany.

    • Peter Nürnberg


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M.H.: subject classification, clinical study, linkage analysis, mapping, mutational screening, writing of the manuscript; S.D.: RTQ-PCR, protein expression, immunoblot; A.O., J.S.: mutational screening; J.K.: mutational screening, protein expression; V.E., A.K., M.M.-G., M.M., D.R.: subject classification, clinical samples and data; R.K., S.T., R.S.: yeast studies, protein expression, enzyme assays; L.O.: microarray expression experiments; F.R., H.T., P.N.: linkage analysis and mapping; J.G.: study design, supervision of clinical, molecular and functional study, writing of the manuscript.

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Correspondence to Jutta Gärtner.

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