Dataset Information

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

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.

SUBMITTER: Ghosh SG

PROVIDER: S-EPMC6128219 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Ghosh Shereen G SG Becker Kerstin K Huang He H Dixon-Salazar Tracy T Chai Guoliang G Salpietro Vincenzo V Al-Gazali Lihadh L Waisfisz Quinten Q Wang Haicui H Vaux Keith K KK Stanley Valentina V Manole Andreea A Akpulat Ugur U Weiss Marjan M MM Efthymiou Stephanie S Hanna Michael G MG Minetti Carlo C Striano Pasquale P Pisciotta Livia L De Grandis Elisa E Altmüller Janine J Nürnberg Peter P Thiele Holger H Yis Uluc U Okur Tuncay Derya TD Polat Ayse Ipek AI Amiri Nafise N Doosti Mohammad M Karimani Ehsan Ghayoor EG Toosi Mehran B MB Haddad Gabriel G Karakaya Mert M Wirth Brunhilde B van Hagen Johanna M JM Wolf Nicole I NI Maroofian Reza R Houlden Henry H Cirak Sebahattin S Gleeson Joseph G JG

American journal of human genetics 20180809 3

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 ...[more]

PMID: 30100084

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Dataset Information

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

Publications

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

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