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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 int...

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Autores principales: Meuwissen, Marije E.C., Schot, Rachel, Buta, Sofija, Oudesluijs, Grétel, Tinschert, Sigrid, Speer, Scott D., Li, Zhi, van Unen, Leontine, Heijsman, Daphne, Goldmann, Tobias, Lequin, Maarten H., Kros, Johan M., Stam, Wendy, Hermann, Mark, Willemsen, Rob, Brouwer, Rutger W.W., Van IJcken, Wilfred F.J., Martin-Fernandez, Marta, de Coo, Irenaeus, Dudink, Jeroen, de Vries, Femke A.T., Bertoli Avella, Aida, Prinz, Marco, Crow, Yanick J., Verheijen, Frans W., Pellegrini, Sandra, Bogunovic, Dusan, Mancini, Grazia M.S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925017/
https://www.ncbi.nlm.nih.gov/pubmed/27325888
http://dx.doi.org/10.1084/jem.20151529
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author Meuwissen, Marije E.C.
Schot, Rachel
Buta, Sofija
Oudesluijs, Grétel
Tinschert, Sigrid
Speer, Scott D.
Li, Zhi
van Unen, Leontine
Heijsman, Daphne
Goldmann, Tobias
Lequin, Maarten H.
Kros, Johan M.
Stam, Wendy
Hermann, Mark
Willemsen, Rob
Brouwer, Rutger W.W.
Van IJcken, Wilfred F.J.
Martin-Fernandez, Marta
de Coo, Irenaeus
Dudink, Jeroen
de Vries, Femke A.T.
Bertoli Avella, Aida
Prinz, Marco
Crow, Yanick J.
Verheijen, Frans W.
Pellegrini, Sandra
Bogunovic, Dusan
Mancini, Grazia M.S.
author_facet Meuwissen, Marije E.C.
Schot, Rachel
Buta, Sofija
Oudesluijs, Grétel
Tinschert, Sigrid
Speer, Scott D.
Li, Zhi
van Unen, Leontine
Heijsman, Daphne
Goldmann, Tobias
Lequin, Maarten H.
Kros, Johan M.
Stam, Wendy
Hermann, Mark
Willemsen, Rob
Brouwer, Rutger W.W.
Van IJcken, Wilfred F.J.
Martin-Fernandez, Marta
de Coo, Irenaeus
Dudink, Jeroen
de Vries, Femke A.T.
Bertoli Avella, Aida
Prinz, Marco
Crow, Yanick J.
Verheijen, Frans W.
Pellegrini, Sandra
Bogunovic, Dusan
Mancini, Grazia M.S.
author_sort Meuwissen, Marije E.C.
collection PubMed
description 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.
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spelling pubmed-49250172016-12-27 Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome Meuwissen, Marije E.C. Schot, Rachel Buta, Sofija Oudesluijs, Grétel Tinschert, Sigrid Speer, Scott D. Li, Zhi van Unen, Leontine Heijsman, Daphne Goldmann, Tobias Lequin, Maarten H. Kros, Johan M. Stam, Wendy Hermann, Mark Willemsen, Rob Brouwer, Rutger W.W. Van IJcken, Wilfred F.J. Martin-Fernandez, Marta de Coo, Irenaeus Dudink, Jeroen de Vries, Femke A.T. Bertoli Avella, Aida Prinz, Marco Crow, Yanick J. Verheijen, Frans W. Pellegrini, Sandra Bogunovic, Dusan Mancini, Grazia M.S. J Exp Med Research Articles 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. The Rockefeller University Press 2016-06-27 /pmc/articles/PMC4925017/ /pubmed/27325888 http://dx.doi.org/10.1084/jem.20151529 Text en © 2016 Meuwissen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Meuwissen, Marije E.C.
Schot, Rachel
Buta, Sofija
Oudesluijs, Grétel
Tinschert, Sigrid
Speer, Scott D.
Li, Zhi
van Unen, Leontine
Heijsman, Daphne
Goldmann, Tobias
Lequin, Maarten H.
Kros, Johan M.
Stam, Wendy
Hermann, Mark
Willemsen, Rob
Brouwer, Rutger W.W.
Van IJcken, Wilfred F.J.
Martin-Fernandez, Marta
de Coo, Irenaeus
Dudink, Jeroen
de Vries, Femke A.T.
Bertoli Avella, Aida
Prinz, Marco
Crow, Yanick J.
Verheijen, Frans W.
Pellegrini, Sandra
Bogunovic, Dusan
Mancini, Grazia M.S.
Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome
title Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome
title_full Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome
title_fullStr Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome
title_full_unstemmed Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome
title_short Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome
title_sort human usp18 deficiency underlies type 1 interferonopathy leading to severe pseudo-torch syndrome
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925017/
https://www.ncbi.nlm.nih.gov/pubmed/27325888
http://dx.doi.org/10.1084/jem.20151529
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