ArticleAmerican journal of human genetics2018
Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.
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Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 40 papers.
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40 citing papers in PubMed, 86 citations in OpenAlex.
- Data-Driven Insights into Hyperkinetic Disorders in Neurodevelopmental Syndromes and Epileptic Encephalopathies.Movement disorders clinical practice · 2026Review
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- Chemical Synthesis of Native ADP-Ribosylated Oligonucleotides Enables Analysis of DNA ADP-Ribosylation Hydrolase Specificity.Journal of the American Chemical Society · 2026Article
- Phenotypic Diversity in Stress-induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures: Novel Associations with Parkinsonism, Icthyosis and Cataract.Cerebellum (London, England) · 2025Article
- Recurrent Paroxysmal Torticollis as a Presenting Feature of Stress-Induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures (CONDSIAS).Indian pediatrics · 2025Article
- Social context prevents heat hormetic effects against mutagens during fish development.FEBS letters · 2025Article
- Novel heterozygous variant ofHeliyon · 2024Article
- Expanding the Spectrum of Stress-Induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures (CONDSIAS).Cerebellum (London, England) · 2024Article
- Regulation of Biomolecular Condensates by Poly(ADP-ribose).Chemical reviews · 2023Review
- The function and regulation of ADP-ribosylation in the DNA damage response.Biochemical Society transactions · 2023Article
- Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling.Nature communications · 2023Article
- Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling.Molecular cell · 2023Article
- ARH Family of ADP-Ribose-Acceptor Hydrolases.Cells · 2022Review
- Reanalysis of exome negative patients with rare disease: a pragmatic workflow for diagnostic applications.Genome medicine · 2022Article
- Inter-Species Rescue of Mutant Phenotype-The Standard for Genetic Analysis of Human Genetic Disorders inInternational journal of molecular sciences · 2022Review
- Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders.Frontiers in molecular biosciences · 2022Review
- BiallelicLife science alliance · 2021Article
- Why structure and chain length matter: on the biological significance underlying the structural heterogeneity of poly(ADP-ribose).Nucleic acids research · 2021Article
- DNA damage and regulation of protein homeostasis.DNA repair · 2021Review
- Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome.Brain sciences · 2021Article
Corrections and comments
- Erratum issued
- Erratum issued
Authors and funding
39 authors at 13 institutions in 8 countries.
Shereen G GhoshLaboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
Kerstin BeckerCenter for Molecular Medicine Cologne, Cologne, Germany; Department of Pediatrics, University Hospital of Cologne, Cologne, Germany; Center for Rare Diseases, Cologne 50937, Germany.
He HuangDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Hospital, San Diego, CA, USA.
Tracy Dixon-SalazarLaboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
Guoliang ChaiLaboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
Vincenzo SalpietroDepartment of Neuromuscular Diseases and Neurogenetics Laboratory, University College of London, London WC1E 6BT, UK.
Lihadh Al-GazaliDepartment of Pediatrics, United Arab Emirates University and Tawam Hospital, PO Box 15551, Al Ain, Abu Dhabi, UAE.
Quinten WaisfiszAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Genetics, De Boelelaan 1117, Amsterdam, the Netherlands.
Haicui WangCenter for Molecular Medicine Cologne, Cologne, Germany; Department of Pediatrics, University Hospital of Cologne, Cologne, Germany; Center for Rare Diseases, Cologne 50937, Germany.
Keith K VauxDivision of Medical Genetics, Department of Medicine, School of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
Valentina StanleyLaboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
Andreea ManoleDepartment of Neuromuscular Diseases and Neurogenetics Laboratory, University College of London, London WC1E 6BT, UK.
Ugur AkpulatCenter for Molecular Medicine Cologne, Cologne, Germany; Department of Pediatrics, University Hospital of Cologne, Cologne, Germany; Kastamonu University, Medical Faculty, 37150 Kastamonu, Turkey.
Marjan M WeissAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Genetics, De Boelelaan 1117, Amsterdam, the Netherlands.
Stephanie EfthymiouDepartment of Neuromuscular Diseases and Neurogenetics Laboratory, University College of London, London WC1E 6BT, UK.
Michael G HannaDepartment of Neuromuscular Diseases and Neurogenetics Laboratory, University College of London, London WC1E 6BT, UK.
Carlo MinettiPediatric Neurology and Muscular Diseases Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, University of Genoa, Genoa 16126, Italy.
Pasquale StrianoPediatric Neurology and Muscular Diseases Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, University of Genoa, Genoa 16126, Italy.
Livia PisciottaChild Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, University of Genoa, Genoa 16126, Italy.
Elisa De GrandisChild Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, University of Genoa, Genoa 16126, Italy.
Janine AltmüllerCologne Center for Genomics, University of Cologne, Cologne 50931, Germany.
Peter NürnbergCologne Center for Genomics, University of Cologne, Cologne 50931, Germany.
Holger ThieleCologne Center for Genomics, University of Cologne, Cologne 50931, Germany.
Uluc YisDepartment of Pediatrics, Division of Child Neurology, Dokuz Eylül University School of Medicine, İzmir 35340, Turkey.
Tuncay Derya OkurDepartment of Pediatrics, Division of Child Neurology, Dokuz Eylül University School of Medicine, İzmir 35340, Turkey.
Ayse Ipek PolatDepartment of Pediatrics, Division of Child Neurology, Dokuz Eylül University School of Medicine, İzmir 35340, Turkey.
Nafise AmiriTargeted Drug Delivery Research Center, Pharmaceutical Technology Institute, University of Medical Sciences, Mashhad 15731, Iran.
Mohammad DoostiNext Generation Genetic Clinic, Mashhad 15731, Iran.
Ehsan Ghayoor KarimaniNext Generation Genetic Clinic, Mashhad 15731, Iran; Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
Mehran B ToosiPediatric Neurology, Department of Pediatric Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 15731, Iran.
Gabriel HaddadDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Hospital, San Diego, CA, USA.
Mert KarakayaInstitute of Human Genetics, Center for Molecular Medicine, and Center for Rare Diseases, University of Cologne, Cologne 50937, Germany.
Brunhilde WirthCenter for Rare Diseases, Cologne 50937, Germany; Institute of Human Genetics, Center for Molecular Medicine, and Center for Rare Diseases, University of Cologne, Cologne 50937, Germany.
Johanna M van HagenAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Genetics, De Boelelaan 1117, Amsterdam, the Netherlands.
Nicole I WolfDepartment of Child Neurology, VU University Medical Center and Amsterdam Neuroscience, Amsterdam 1117, the Netherlands.
Reza MaroofianMolecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
Henry HouldenDepartment of Neuromuscular Diseases and Neurogenetics Laboratory, University College of London, London WC1E 6BT, UK.
Sebahattin CirakCenter for Molecular Medicine Cologne, Cologne, Germany; Department of Pediatrics, University Hospital of Cologne, Cologne, Germany; Center for Rare Diseases, Cologne 50937, Germany. Electronic address: sebahattin.cirak@uk-koeln.de.
Joseph G GleesonLaboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA. Electronic address: jogleeson@ucsd.edu.
University of Cologne · DEChildren’s Institute · USUniversity College London · GBIstituto Giannina Gaslini · ITAmsterdam University Medical Centers · NLDokuz Eylül University · TRUniversity Hospital Cologne · DEMashhad University of Medical Sciences · IRSt George's, University of London · GBUniversity of California San Diego · USAmsterdam Neuroscience · NLUnited Arab Emirates University · AEUniversity of California San Diego Medical Center · US
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MYale Center for Mendelian DisordersU54HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2012 to 2015
$11.0MTraining Program in Basic Clinical GeneticsT32GM008666 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAMILTON, BRUCE A · 1998 to 2021
$8.6MMolecular Characterization of Joubert SyndromeR01NS048453 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G · 2004 to 2020
$6.0MJouberin and Nephrocystin in Joubert SyndromeR01NS052455 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G · 2007 to 2015
$3.0MMolecular mechanisms of the ADPRHL2-mediated pediatric neurodegenerative diseaseF31HD095602 · NICHD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GHOSH, SHEREEN G. · 2018 to 2020
$116kMedical Research Council G0601943Medical Research Council MR/K000608/1NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54 HG006504NHGRI NIH HHS UM1 HG008900NICHD NIH HHS F31 HD095602NIGMS NIH HHS T32 GM008666NINDS NIH HHS R01 NS048453NINDS NIH HHS R01 NS052455Wellcome Trust
Abstract
ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.
Indexed as
ADPRHL2ADP-ribosylationARH3ataxiaepilepsyneurodegenerationneuropathyoxidative stresspoly-ADP riboseSUDEP
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