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Am J Hum Genet. 2018 Sep 6;103(3):431-439. doi: 10.1016/j.ajhg.2018.07.010. Epub 2018 Aug 9.

Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.

Author information

1
Laboratory 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.
2
Center for Molecular Medicine Cologne, Cologne, Germany; Department of Pediatrics, University Hospital of Cologne, Cologne, Germany; Center for Rare Diseases, Cologne 50937, Germany.
3
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Hospital, San Diego, CA, USA.
4
Department of Neuromuscular Diseases and Neurogenetics Laboratory, University College of London, London WC1E 6BT, UK.
5
Department of Pediatrics, United Arab Emirates University and Tawam Hospital, PO Box 15551, Al Ain, Abu Dhabi, UAE.
6
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Genetics, De Boelelaan 1117, Amsterdam, the Netherlands.
7
Division of Medical Genetics, Department of Medicine, School of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
8
Center for Molecular Medicine Cologne, Cologne, Germany; Department of Pediatrics, University Hospital of Cologne, Cologne, Germany; Kastamonu University, Medical Faculty, 37150 Kastamonu, Turkey.
9
Pediatric 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.
10
Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, University of Genoa, Genoa 16126, Italy.
11
Cologne Center for Genomics, University of Cologne, Cologne 50931, Germany.
12
Department of Pediatrics, Division of Child Neurology, Dokuz Eylül University School of Medicine, İzmir 35340, Turkey.
13
Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, University of Medical Sciences, Mashhad 15731, Iran.
14
Next Generation Genetic Clinic, Mashhad 15731, Iran.
15
Next Generation Genetic Clinic, Mashhad 15731, Iran; Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
16
Pediatric Neurology, Department of Pediatric Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 15731, Iran.
17
Institute of Human Genetics, Center for Molecular Medicine, and Center for Rare Diseases, University of Cologne, Cologne 50937, Germany.
18
Center 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.
19
Department of Child Neurology, VU University Medical Center and Amsterdam Neuroscience, Amsterdam 1117, the Netherlands.
20
Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
21
Center 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.
22
Laboratory 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.

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.

KEYWORDS:

ADP-ribosylation; ADPRHL2; ARH3; SUDEP; ataxia; epilepsy; neurodegeneration; neuropathy; oxidative stress; poly-ADP ribose

PMID:
30100084
PMCID:
PMC6128219
[Available on 2019-03-06]
DOI:
10.1016/j.ajhg.2018.07.010

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