Skip to Main content Skip to Navigation
Journal articles

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

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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [35 references]  Display  Hide  Download

https://hal-pasteur.archives-ouvertes.fr/pasteur-02070980
Contributor : Zhi Li <>
Submitted on : Monday, March 18, 2019 - 12:41:56 PM
Last modification on : Wednesday, May 20, 2020 - 9:22:02 PM
Long-term archiving on: : Wednesday, June 19, 2019 - 2:09:29 PM

Licence


Distributed under a Creative Commons Attribution - NonCommercial - ShareAlike 4.0 International License

Identifiers

Citation

Marije E.C. Meuwissen, Rachel Schot, Sofija Buta, Grétel Oudesluijs, Sigrid Tinschert, et al.. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. Journal of Experimental Medicine, Rockefeller University Press, 2016, 213 (7), pp.1163-1174. ⟨10.1084/jem.20151529⟩. ⟨pasteur-02070980⟩

Share

Metrics

Record views

301

Files downloads

799