Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome.
Marije E C MeuwissenRachel SchotSofija ButaGrétel OudesluijsSigrid TinschertScott D SpeerZhi LiLeontine M van UnenDaphne HeijsmanTobias GoldmannMaarten H LequinJohan M KrosWendy StamMark HermannRob WillemsenRutger W W BrouwerWilfred F J Van IJckenMarta Martín-FernándezIrenaeus F M de CooJeroen DudinkFemke A T de VriesAida Bertoli AvellaMarco PrinzYanick J CrowFrans W VerheijenSandra PellegriniDusan BogunovicGrazia M S ManciniPublished in: The Journal of experimental medicine (2016)
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.
Keyphrases
- dendritic cells
- immune response
- chronic kidney disease
- case report
- end stage renal disease
- genome wide
- oxidative stress
- innate immune
- copy number
- intellectual disability
- ejection fraction
- newly diagnosed
- endothelial cells
- prognostic factors
- replacement therapy
- small molecule
- blood brain barrier
- gene expression
- pregnant women
- resting state
- transcription factor
- functional connectivity
- autism spectrum disorder
- muscular dystrophy