Dyschromatosis Symmetrica Hereditaria and Aicardi-Goutières Syndrome 6 Are Phenotypic Variants Caused by ADAR1 Mutations

Kono, Michihiro; Matsumoto, Fumi; Suzuki, Yasuhiro; Suganuma, Mutsumi; Saitsu, Hirotomo; Ito, Yosoji; Fujiwara, Sakuhei; Moriwaki, Shinichi; Matsumoto, K; Matsumoto, Naomichi; Tomita, Yasushi; Sugiura, Kazumitsu; Akiyama, Masashi

doi:10.1016/j.jid.2015.12.034

Cited by 40 publications

(34 citation statements)

References 8 publications

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“…The local institutional review board approved this study, and all the participants provided written informed consent. Mutation analysis as previously reported identified the compound heterozygous ADAR1 mutations p.Pro193Ala (paternal) and p.Cys1036Ser (maternal) (Fig. g).…”

supporting

confidence: 70%

“…The ADAR1 mutation p.Pro193Ala detected in the present study has been frequently seen in both BSN and AGS cohorts. Indeed, 11 of the 13 patients with BSN or AGS6 with compound heterozygous ADAR1 mutations that have been reported to date had p.Pro193Ala . The p.Pro193Ala mutation has been recorded in 41 out of 6553 individuals annotated in the Exome Variant Server database.…”

mentioning

confidence: 99%

“…We evaluated the RNA editing ability of several mutant ADAR1 p150 isoforms including homozygous and heterozygous p.Pro193Ala, as previously reported . (A figure detailing the A–I editing efficiencies is available from the authors on request.)…”

mentioning

confidence: 99%

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Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression

et al. 2018

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supporting

confidence: 70%

mentioning

confidence: 99%

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Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression

et al. 2018

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“…The frequent observation of stop and frameshift variants in DSH indicates haploinsufficiency as the likely molecular pathology, consistent with the recent confirmation of our previous suggestion that two individuals with DSH would be at one in four risk of a pregnancy with ADAR1-related neurological disease. 16 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…In general, only nine mutations on the ADAR1 coding sequence have been identified in AGS patients, compared to the more than 130 amino acids that have been found to be mutated in DSH patients. In addition to Hayashi et al′s list of known mutations [39], novel mutations in ADAR1 that are associated with DSH have also been identified [40,41,42,43,44,45], including an in-frame insertion that leads to mis-splicing [43]. …”

Section: Adar1′s Role In Immunitymentioning

confidence: 99%

Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases

Song

Sakurai

Shiromoto

et al. 2016

Genes

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Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA (dsRNA). Among the three types of mammalian ADARs, ADAR1 has long been recognized as an essential enzyme for normal development. The interferon-inducible ADAR1p150 is involved in immune responses to both exogenous and endogenous triggers, whereas the functions of the constitutively expressed ADAR1p110 are variable. Recent findings that ADAR1 is involved in the recognition of self versus non-self dsRNA provide potential explanations for its links to hematopoiesis, type I interferonopathies, and viral infections. Editing in both coding and noncoding sequences results in diseases ranging from cancers to neurological abnormalities. Furthermore, editing of noncoding sequences, like microRNAs, can regulate protein expression, while editing of Alu sequences can affect translational efficiency and editing of proximal sequences. Novel identifications of long noncoding RNA and retrotransposons as editing targets further expand the effects of A-to-I editing. Besides editing, ADAR1 also interacts with other dsRNA-binding proteins in editing-independent manners. Elucidating the disease-specific patterns of editing and/or ADAR1 expression may be useful in making diagnoses and prognoses. In this review, we relate the mechanisms of ADAR1′s actions to its pathological implications, and suggest possible mechanisms for the unexplained associations between ADAR1 and human diseases.

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Dyschromatosis Symmetrica Hereditaria and Aicardi-Goutières Syndrome 6 Are Phenotypic Variants Caused by ADAR1 Mutations

Abstract: JC, et al. Engineering of large numbers of highly specific homing endonucleases that induce recombination on novel DNA targets. J Mol Biol 2006;355: 443e58. Bruckner-Tuderman L. Dystrophic epidermolysis bullosa: pathogenesis and clinical features. Dermatol Clin 2010;28:107e14.

Cited by 40 publications

References 8 publications

Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression

Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression

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

Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases

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