Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome

J Exp Med. 2016 Jun 27;213(7):1163-74. doi: 10.1084/jem.20151529.

Marije E C Meuwissen ¹, Rachel Schot ¹, Sofija Buta ², Grétel Oudesluijs ¹, Sigrid Tinschert ³, Scott D Speer ², Zhi Li ⁴, Leontine van Unen ¹, Daphne Heijsman ⁵, Tobias Goldmann ⁶, Maarten H Lequin ⁷, Johan M Kros ⁸, Wendy Stam ¹, Mark Hermann ², Rob Willemsen ¹, Rutger W W Brouwer ⁹, Wilfred F J Van IJcken ⁹, Marta Martin-Fernandez ², Irenaeus de Coo ¹⁰, Jeroen Dudink ¹¹, Femke A T de Vries ¹, Aida Bertoli Avella ¹, Marco Prinz ¹², Yanick J Crow ¹³, Frans W Verheijen ¹, Sandra Pellegrini ⁴, Dusan Bogunovic ¹⁴, Grazia M S Mancini ¹⁵

Affiliations

1 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
2 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
3 Medical Faculty Carl Gustav Carus, Technical University of Dresden, 01069 Dresden, Germany Division of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria.
4 Institut Pasteur, Cytokine Signaling Unit, Centre National de la Recherche Scientifique URA 1961, INSERM U 1221, 75724, Paris, France.
5 Department of Bioinformatics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
6 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
7 Department of Radiology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
8 Department of Pathology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
9 Erasmus Center for Biomics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
10 Department of Child Neurology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
11 Department of Neonatology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
12 Institute of Neuropathology and BIOSS Center for Biological Signaling Studies, University of Freiburg, 79085 Freiburg, Germany.
13 INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Necker Hospital, Paris Descartes University, 75015 Paris, France Manchester Centre for Genomic Medicine and Academic Health Science Centre, University of Manchester, Manchester M13 9PL, England, UK.
14 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 g.mancini@erasmusmc.nl Dusan.Bogunovic@mssm.edu.
15 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands g.mancini@erasmusmc.nl Dusan.Bogunovic@mssm.edu.

PMID: 27325888 DOI: 10.1084/jem.20151529

Abstract

Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital Infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.

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