Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with n...

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Detalhes bibliográficos
Autores: Rice, Gillian I, Rodríguez-Pombo, Pilar, Crow, Yanick J.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/166024
Acesso em linha:http://hdl.handle.net/10261/166024
Access Level:acceso abierto
Palavra-chave:Bilateral striatal necrosis
Spastic paraparesis
Dystonia
Idiopathic basal ganglia calcification
Aicardi–Goutières syndrome
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spelling Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological DiseaseRice, Gillian IRodríguez-Pombo, PilarCrow, Yanick J.Bilateral striatal necrosisSpastic paraparesisDystoniaIdiopathic basal ganglia calcificationAicardi–Goutières syndromeWe investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.European Research Council (GA 309449: Fellowship to Y.J.C.), ERA-NET Neuron (MR/M501803/1), and a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” (ANR-10-IAHU-01)Peer ReviewedThiemeEuropean Research CouncilAgence Nationale de la Recherche (France)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2018201820172018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/166024reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1660242026-05-22T06:33:51Z
dc.title.none.fl_str_mv Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
title Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
spellingShingle Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
Rice, Gillian I
Bilateral striatal necrosis
Spastic paraparesis
Dystonia
Idiopathic basal ganglia calcification
Aicardi–Goutières syndrome
title_short Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
title_full Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
title_fullStr Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
title_full_unstemmed Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
title_sort Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
dc.creator.none.fl_str_mv Rice, Gillian I
Rodríguez-Pombo, Pilar
Crow, Yanick J.
author Rice, Gillian I
author_facet Rice, Gillian I
Rodríguez-Pombo, Pilar
Crow, Yanick J.
author_role author
author2 Rodríguez-Pombo, Pilar
Crow, Yanick J.
author2_role author
author
dc.contributor.none.fl_str_mv European Research Council
Agence Nationale de la Recherche (France)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Bilateral striatal necrosis
Spastic paraparesis
Dystonia
Idiopathic basal ganglia calcification
Aicardi–Goutières syndrome
topic Bilateral striatal necrosis
Spastic paraparesis
Dystonia
Idiopathic basal ganglia calcification
Aicardi–Goutières syndrome
description We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/166024
url http://hdl.handle.net/10261/166024
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Thieme
publisher.none.fl_str_mv Thieme
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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