Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome.
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.
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Marije E C
0000-0001-9226-8159
ME
Meuwissen
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Rachel
0000-0001-9578-4095
R
Schot
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Sofija
0000-0001-7662-3851
S
Buta
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Grétel
G
Oudesluijs
Medical Faculty Carl Gustav Carus, Technical University of Dresden, 01069 Dresden, Germany Division of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria.
Sigrid
0000-0001-7256-2481
S
Tinschert
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Scott D
0000-0002-7584-5265
SD
Speer
Institut Pasteur, Cytokine Signaling Unit, Centre National de la Recherche Scientifique URA 1961, INSERM U 1221, 75724, Paris, France.
Zhi
Z
Li
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Leontine
0000-0003-1174-9140
L
van Unen
Department of Bioinformatics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Daphne
D
Heijsman
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Tobias
0000-0001-9754-9144
T
Goldmann
Department of Radiology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Maarten H
0000-0001-7488-1734
MH
Lequin
Department of Pathology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Johan M
0000-0002-4727-0724
JM
Kros
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Wendy
0000-0002-7470-847X
W
Stam
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Mark
M
Hermann
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Rob
R
Willemsen
Erasmus Center for Biomics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Rutger W W
RW
Brouwer
Erasmus Center for Biomics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Wilfred F J
0000-0002-0421-8301
WF
Van IJcken
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Marta
0000-0003-4671-6349
M
Martin-Fernandez
Department of Child Neurology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Irenaeus
0000-0003-0533-7422
I
de Coo
Department of Neonatology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Jeroen
0000-0003-0446-3646
J
Dudink
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Femke A T
0000-0002-3991-1800
FA
de Vries
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Aida
A
Bertoli Avella
Institute of Neuropathology and BIOSS Center for Biological Signaling Studies, University of Freiburg, 79085 Freiburg, Germany.
Marco
M
Prinz
INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Necker Hospital, Paris Descartes University, 75015 Paris, France Manchester Centre for Genomic Medicine and Academic Health Science Centre, University of Manchester, Manchester M13 9PL, England, UK.
Yanick J
YJ
Crow
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
Frans W
FW
Verheijen
Institut Pasteur, Cytokine Signaling Unit, Centre National de la Recherche Scientifique URA 1961, INSERM U 1221, 75724, Paris, France.
Sandra
0000-0001-5837-7589
S
Pellegrini
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 g.mancini@erasmusmc.nl Dusan.Bogunovic@mssm.edu.
Dusan
D
Bogunovic
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands g.mancini@erasmusmc.nl Dusan.Bogunovic@mssm.edu.
Grazia M S
GM
Mancini
D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D002114:Calcinosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010450:Endopeptidases / Q000172:deficiency* / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D008297:Male; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009421:Nervous System Malformations / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D043222:Ubiquitin Thiolesterase
D007370:Interferon Type I; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase