Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 7, Pages 1163-1174Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151529
Keywords
-
Categories
Funding
- NutsOhra Funds project [1203-030]
- National Institute of Allergy and Infectious Diseases [R00AI106942-02]
Ask authors/readers for more resources
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-Goutieres 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available