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

Abstract

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.

Keywords

Aicardi–Goutières syndrome - bilateral striatal necrosis - spastic paraparesis - dystonia - idiopathic basal ganglia calcification

Funding

Y.J.C. acknowledges funding from the 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). T.A.B. acknowledges funding from the NIHR. V.N. and K.M.R. acknowledge the clinical support of the C4RCD Research Group.

• References

• 1 Liddicoat BJ, Chalk AM, Walkley CR. ADAR1, inosine and the immune sensing system: distinguishing self from non-self. Wiley Interdiscip Rev RNA 2016; 7 (02) 157-172
• 2 Hartner JC, Walkley CR, Lu J, Orkin SH. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol 2009; 10 (01) 109-115
• 3 Liddicoat BJ, Piskol R, Chalk AM. , et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 2015; 349 (6252): 1115-1120
• 4 Pestal K, Funk CC, Snyder JM, Price ND, Treuting PM, Stetson DB. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity 2015; 43 (05) 933-944
• 5 Rice GI, Kasher PR, Forte GM. , et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet 2012; 44 (11) 1243-1248
• 6 Livingston JH, Lin JP, Dale RC. , et al. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet 2014; 51 (02) 76-82
• 7 Crow YJ, Zaki MS, Abdel-Hamid MS. , et al. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics 2014; 45 (06) 386-393
• 8 La Piana R, Uggetti C, Olivieri I. , et al. Bilateral striatal necrosis in two subjects with Aicardi-Goutières syndrome due to mutations in ADAR1 (AGS6). Am J Med Genet A 2014; 164A [phone]
• 9 La Piana R, Uggetti C, Roncarolo F. , et al. Neuroradiologic patterns and novel imaging findings in Aicardi-Goutières syndrome. Neurology 2016; 86 (01) 28-35
• 10 Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997; 39 (04) 214-223
• 11 Eliasson AC, Krumlinde-Sundholm L, Rösblad B. , et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child Neurol 2006; 48 (07) 549-554
• 12 Hidecker MJ, Paneth N, Rosenbaum PL. , et al. Developing and validating the Communication Function Classification System for individuals with cerebral palsy. Dev Med Child Neurol 2011; 53 (08) 704-710
• 13 Tojo K, Sekijima Y, Suzuki T. , et al. Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation. Mov Disord 2006; 21 (09) 1510-1513
• 14 Heale BS, Keegan LP, McGurk L. , et al. Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO J 2009; 28 (20) 3145-3156
• 15 Hayashi M, Suzuki T. Dyschromatosis symmetrica hereditaria. J Dermatol 2013; 40 (05) 336-343
• 16 Kono M, Matsumoto F, Suzuki Y. , et al. Dyschromatosis symmetrica hereditaria and Aicardi-Goutières syndrome 6 are phenotypic variants caused by ADAR1 mutations. J Invest Dermatol 2016; 136 (04) 875-878
• 17 Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 2011; 1238: 91-98
• 18 Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol 2015; 15 (07) 429-440
• 19 Crow YJ, Chase DS, Lowenstein Schmidt J. , et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A 2015; 167A [phone]
• 20 Rice GI, Forte GM, Szynkiewicz M. , et al. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol 2013; 12 (12) 1159-1169
• 21 Rice GI, Melki I, Frémond ML. , et al. Assessment of type I interferon signaling in pediatric inflammatory disease. J Clin Immunol 2017; 37 (02) 123-132
• 22 Toth AM, Li Z, Cattaneo R, Samuel CE. RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR. J Biol Chem 2009; 284 (43) 29350-29356
• 23 Kavanagh D, McGlasson S, Jury A. , et al. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood 2016; 128 (24) 2824-2833
• 24 Akwa Y, Hassett DE, Eloranta ML. , et al. Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J Immunol 1998; 161 (09) 5016-5026
• 25 Campbell IL, Krucker T, Steffensen S. , et al. Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha. Brain Res 1999; 835 (01) 46-61
• 26 Barlow CF, Priebe CJ, Mulliken JB. , et al. Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr 1998; 132 (3 Pt 1): 527-530
• 27 Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope 2004; 114 (07) 1231-1236
• 28 Vitali P, Scadden AD. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis. Nat Struct Mol Biol 2010; 17 (09) 1043-1050
• 29 Frémond ML, Rodero MP, Jeremiah N. , et al. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol 2016; 138 (06) 1752-1755