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

Marije E C Meuwissen, Rachel Schot, Sofija Buta, Grétel Oudesluijs, Sigrid Tinschert, Scott D. Speer, Zhi Li, Leontine van Unen, Daphne Heijsman, Tobias Goldmann, Maarten H. Lequin, Johan M. Kros, Wendy Stam, Mark Hermann, Rob Willemsen, Rutger W W Brouwer, Wilfred F J Van IJcken, Marta Martin-Fernandez, Irenaeus de Coo, Jeroen DudinkFemke A T de Vries, Aida Bertoli Avella, Marco Prinz, Yanick Crow, Frans W. Verheijen, Sandra Pellegrini, Dusan Bogunovic, Grazia M S Mancini

    Research output: Contribution to journalArticlepeer-review


    Pseudo-TOR CH 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.

    Original languageEnglish
    Pages (from-to)1163-1174
    Number of pages12
    JournalJournal of Experimental Medicine
    Issue number7
    Publication statusPublished - 20 Jun 2016


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