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

Ghosh, S. G. and Becker, K. and Huang, H. and Dixon-Salazar, T. and Chai, G. and Salpietro, V. and Al-Gazali, L. and Waisfisz, Q. and Wang, H. and Vaux, K. K. and Stanley, V. and Manole, A. and Akpulat, U. and Weiss, M. M. and Efthymiou, S. and Hanna, M. G. and Minetti, C. and Striano, P. and Pisciotta, L. and De Grandis, E. and Altmüller, J. and Nürnberg, P. and Thiele, H. and Yis, U. and Okur, T. D. and Polat, A. I. and Amiri, N. and Doosti, M. and Karimani, E. G. and Toosi, M. B. and Haddad, G. and Karakaya, M. and Wirth, B. and van Hagen, J. M. and Wolf, N. I. and Maroofian, R. and Houlden, H. and Cirak, S. and Gleeson, J. G. (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 (3). pp. 431-439.

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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. © 2018

Item Type: Article
Additional Information: Cited By :7 Export Date: 16 February 2020 CODEN: AJHGA Correspondence Address: Cirak, S.; Center for Molecular Medicine CologneGermany; email: sebahattin.cirak@uk-koeln.de
Uncontrolled Keywords: ADP-ribosylation ADPRHL2 ARH3 ataxia epilepsy neurodegeneration neuropathy oxidative stress poly-ADP ribose SUDEP ADP ribosylhydrolase 3 cysteine hydrolase leucine nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor serine threonine unclassified drug ADPRHL2 gene amino acid substitution Article biallelic mutation brain atrophy child chromosome 1p clinical feature controlled study degenerative disease developmental delay disease course Drosophila melanogaster electromyography epilepsy ataxia syndrome exon female frameshift mutation gene gene deletion gene frequency gene locus gene mapping gene mutation genetic variability hearing impairment homozygosity human infection intellectual impairment linkage analysis male missense mutation paralogy pharmacological blocking phenotype priority journal protein folding seizure stop codon stress whole exome sequencing whole genome sequencing
Subjects: WL Nervous system
WS Pediatrics
QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: lib2 lib2 lib2
Date Deposited: 20 May 2020 05:25
Last Modified: 20 May 2020 05:25
URI: http://eprints.mums.ac.ir/id/eprint/17303

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