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

Rice, Gillian I.; Kitabayashi, Naoki; Barth, Magalie; Briggs, Tracy A; Burton, Annabel C.E.; Carpanelli, Maria Luisa; Cerisola, Alfredo M.; Colson, Cindy; Dale, Russell C.; Danti, Federica Rachele; Darín, Niklas; Azua, Begoña De; Giorgis, Valentina De; Goede, Christian G E L De; Desguerre, Isabelle; Laet, Corinne De; Eslahi, Atieh; Fahey, Michael; Fallon, Penny; Fay, Alexander; Fazzi, Elisa; Gorman, Mark; Gowrinathan, Nirmala Rani; Hully, Marie; Kurian, Manju A.; Leboucq, Nicolas; Lin, Jean-Pierre; Lines, Matthew A.; Mar, Soe; Maroofian, Reza; Martí-Sánchez, Laura; McCullagh, Gary; Mojarrad, Majid; Narayanan, Vinodh; Orcesi, Simona; Ortigoza‐Escobar, Juan Darío; Pérez‐Dueñas, Belén; Petit, Florence; Ramsey, Keri; Rasmussen, Magnhild; Rivier, François; Rodríguez‐Pombo, Pilar; Roubertie, Agathe; Stödberg, Tommy; Toosi, Mehran Beiraghi; Toutain, Annick; Uettwiller, Florence; Ulrick, Nicole; Vanderver, Adeline; Waldman, Amy; Livingston, John H.; Crow, Yanick J.

doi:10.1055/s-0037-1601449

Cited by 76 publications

(119 citation statements)

References 28 publications

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“…Exome sequencing revealed compound heterozygous pathogenic ADAR variants c.577C>G;p.Pro193Ala (paternally derived) and c.3202+1G>A (maternally derived), as previously reported 9. The p.Pro193Ala substitution represents the most frequent pathogenic variant in ADAR so far identified,10 while the canonical splice-site variant is not recorded in control databases (https://gnomad.broadinstitute.org/).…”

Section: Case Reportssupporting

confidence: 69%

Cardiac valve involvement in ADAR-related type I interferonopathy

et al. 2019

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BackgroundAdenosine deaminases acting on RNA (ADAR) mutations cause a spectrum of neurological phenotypes ranging from severe encephalopathy (Aicardi-Goutières syndrome) to isolated spastic paraplegia and are associated with enhanced type I interferon signalling. In children, non-neurological involvement in the type I interferonopathies includes autoimmune and rheumatological phenomena, with calcifying cardiac valve disease only previously reported in the context of MDA5 gain-of-function.ResultsWe describe three patients with biallelic ADAR mutations who developed calcifying cardiac valvular disease in late childhood (9.5–14 years). Echocardiography revealed progressive calcification of the valvular leaflets resulting in valvular stenosis and incompetence. Two patients became symptomatic with biventricular failure after 5–6.5 years. In one case, disease progressed to severe cardiac failure despite maximal medical management, with death occurring at 17 years. Another child received mechanical mitral and aortic valve replacement at 16 years with good postoperative outcome. Histological examination of the affected valves showed fibrosis and calcification.ConclusionsType I interferonopathies of differing genetic aetiology demonstrate an overlapping phenotypic spectrum which includes calcifying cardiac valvular disease. Individuals with ADAR-related type I interferonopathy may develop childhood-onset multivalvular stenosis and incompetence which can progress insidiously to symptomatic, and ultimately fatal, cardiac failure. Regular surveillance echocardiograms are recommended to detect valvular disease early.

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Section: Case Reportssupporting

confidence: 69%

Cardiac valve involvement in ADAR-related type I interferonopathy

et al. 2019

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“…The consequences of altered ADAR1 function are severe, from embryonic lethality in mice to debilitating neurological disease and systemic interferonopathy in humans with loss-of-function alleles [ 22 , 52 ], to putative oncogenic roles when overexpressed [ 31 , 53 , 54 ], so it is critical to clearly define the key function(s) of ADAR1. In contrast to the physiologically essential role of transcript recoding by ADAR2, the importance of recoding to the biology of ADAR1 was unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Mice homozygous for a single amino acid substitution resulting in an editing-deficient ADAR1 protein ( Adar1 E861A/E861A ) die at E13.5, with remarkably similar phenotypes to the null allele [ 19 ]. Activation of the innate immune sensing system, termed an interferonopathy, is observed in the subset of Aicardi-Goutières syndrome (AGS) patients who harbor mutations in ADAR , demonstrating that the transcriptional response to loss of ADAR1 activity is conserved across mammals [ 17 , 20 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis

et al. 2017

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BackgroundAdenosine-to-inosine (A-to-I) editing of dsRNA by ADAR proteins is a pervasive epitranscriptome feature. Tens of thousands of A-to-I editing events are defined in the mouse, yet the functional impact of most is unknown. Editing causing protein recoding is the essential function of ADAR2, but an essential role for recoding by ADAR1 has not been demonstrated. ADAR1 has been proposed to have editing-dependent and editing-independent functions. The relative contribution of these in vivo has not been clearly defined. A critical function of ADAR1 is editing of endogenous RNA to prevent activation of the dsRNA sensor MDA5 (Ifih1). Outside of this, how ADAR1 editing contributes to normal development and homeostasis is uncertain.ResultsWe describe the consequences of ADAR1 editing deficiency on murine homeostasis. Adar1 E861A/E861A Ifih1 -/- mice are strikingly normal, including their lifespan. There is a mild, non-pathogenic innate immune activation signature in the Adar1 E861A/E861A Ifih1 -/- mice. Assessing A-to-I editing across adult tissues demonstrates that outside of the brain, ADAR1 performs the majority of editing and that ADAR2 cannot compensate in its absence. Direct comparison of the Adar1 -/- and Adar1 E861A/E861A alleles demonstrates a high degree of concordance on both Ifih1 +/+ and Ifih1 -/- backgrounds, suggesting no substantial contribution from ADAR1 editing-independent functions.ConclusionsThese analyses demonstrate that the lifetime absence of ADAR1-editing is well tolerated in the absence of MDA5. We conclude that protein recoding arising from ADAR1-mediated editing is not essential for organismal homeostasis. Additionally, the phenotypes associated with loss of ADAR1 are the result of RNA editing and MDA5-dependent functions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1301-4) contains supplementary material, which is available to authorized users.

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“…Previous studies in mouse showed that ADAR is implicated in erythropoiesis [67;68]. ADAR heterozygous mutations are been found in dyschromatosis symmetrica hereditaria [69] and homozygous or compound heterozygous variations in Aicardi-Goutières syndrome [70].…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing for diagnosis of congenital hemolytic anemia

Mansour‐Hendili

Aissat

Badaoui

et al. 2020

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Background: Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis. Results: A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients. Conclusion: The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients’ healthcare and probably has to be democratized notably for complex cases. .

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

Cited by 76 publications

References 28 publications

Cardiac valve involvement in ADAR-related type I interferonopathy

Cardiac valve involvement in ADAR-related type I interferonopathy

Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis

Exome sequencing for diagnosis of congenital hemolytic anemia

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