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. Epub 2016 Jun 20.


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.

Publication types

  • Clinical Trial

MeSH terms

  • Autoimmune Diseases of the Nervous System* / genetics
  • Autoimmune Diseases of the Nervous System* / immunology
  • Autoimmune Diseases of the Nervous System* / pathology
  • Brain / immunology*
  • Brain / pathology
  • Calcinosis* / genetics
  • Calcinosis* / immunology
  • Calcinosis* / pathology
  • Endopeptidases / deficiency*
  • Endopeptidases / immunology
  • Female
  • Humans
  • Immunity, Innate*
  • Interferon Type I / genetics
  • Interferon Type I / immunology*
  • Male
  • Microglia / immunology*
  • Microglia / pathology
  • Nervous System Malformations* / genetics
  • Nervous System Malformations* / immunology
  • Nervous System Malformations* / pathology
  • Signal Transduction* / genetics
  • Signal Transduction* / immunology
  • Ubiquitin Thiolesterase


  • Interferon Type I
  • Endopeptidases
  • USP18 protein, human
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Aicardi-Goutieres syndrome