UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Ghosh, SG; Becker, K; Huang, H; Dixon-Salazar, T; Chai, G; Salpietro, V; Al-Gazali, L; ... Gleeson, JG; + view all (2018) Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome. American Journal of Human Genetics , 103 (5) pp. 431-439. 10.1016/j.ajhg.2018.07.010. Green open access

[thumbnail of Article]
Preview
Text (Article)
Ghosh_Manuscript for Submission ver 8-SC and SG edits-22-05-2018.pdf - Accepted Version

Download (215kB) | Preview
[thumbnail of Supplemental Text]
Preview
Text (Supplemental Text)
Ghosh_Supplemental Text v7.pdf - Accepted Version

Download (2MB) | Preview

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.

Type: Article
Title: Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajhg.2018.07.010
Publisher version: https://doi.org/10.1016/j.ajhg.2018.07.010
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: ADPRHL2, ARH3, ADP-ribosylation, poly-ADP ribose, oxidative stress, neurodegeneration, epilepsy, ataxia, neuropathy, SUDEP
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10062251
Downloads since deposit
119Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item