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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; Waisfisz, Q; Wang, H; Vaux, KK; et al. Ghosh, SG; Becker, K; Huang, H; Dixon-Salazar, T; Chai, G; Salpietro, V; Al-Gazali, L; Waisfisz, Q; Wang, H; Vaux, KK; Stanley, V; Manole, A; Akpulat, U; Weiss, MM; Efthymiou, S; Hanna, MG; Minetti, C; Striano, P; Pisciotta, L; De Grandis, E; Altmüller, J; Weixler, L; Nürnberg, P; Thiele, H; Yis, U; Okur, TD; Polat, AI; Amiri, N; Doosti, M; Karimani, EG; Toosi, MB; Haddad, G; Karakaya, M; Wirth, B; van Hagen, JM; Wolf, NI; Maroofian, R; Houlden, H; Cirak, S; Gleeson, JG (2018) Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome. Am J Hum Genet, 103 (3). pp. 431-439. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2018.07.010
SGUL Authors: Maroofian, Reza

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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.

Item Type: Article
Additional Information: © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ Corrections available at https://doi.org/10.1016/j.ajhg.2018.10.002 and https://doi.org/10.1016/j.ajhg.2018.07.010
Keywords: ADP-ribosylation, ADPRHL2, ARH3, SUDEP, ataxia, epilepsy, neurodegeneration, neuropathy, oxidative stress, poly-ADP ribose, ADP-ribosylation, ADPRHL2, ARH3, SUDEP, ataxia, epilepsy, neurodegeneration, neuropathy, oxidative stress, poly-ADP ribose, Genetics & Heredity, 06 Biological Sciences, 11 Medical and Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
6 September 2018Published
9 August 2018Published Online
15 July 2018Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
UM1 HG008900NHGRI NIH HHSUNSPECIFIED
U54 HG003067NHGRI NIH HHSUNSPECIFIED
MR/K000608/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
R01 NS048453NINDS NIH HHSUNSPECIFIED
U54 HG006504NHGRI NIH HHSUNSPECIFIED
R01 NS052455NINDS NIH HHSUNSPECIFIED
T32 GM008666NIGMS NIH HHSUNSPECIFIED
WT093205MAWellcome Trusthttp://dx.doi.org/10.13039/100004440
F31 HD095602NICHD NIH HHSUNSPECIFIED
G0601943Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
CI 218/1-1Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
WT104033AIAWellcome Trusthttp://dx.doi.org/10.13039/100004440
2012-305121Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
PubMed ID: 30100084
Web of Science ID: WOS:000443819500012
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112014
Publisher's version: https://doi.org/10.1016/j.ajhg.2018.07.010

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