@article{1cbcdad59fb9448abc3204b3a1ebf4df,
title = "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.",
keywords = "ADP-ribosylation, ADPRHL2, ARH3, SUDEP, ataxia, epilepsy, neurodegeneration, neuropathy, oxidative stress, poly-ADP ribose",
author = "Ghosh, {Shereen G.} and Kerstin Becker and He Huang and Tracy Dixon-Salazar and Guoliang Chai and Vincenzo Salpietro and Lihadh Al-Gazali and Quinten Waisfisz and Haicui Wang and Vaux, {Keith K.} and Valentina Stanley and Andreea Manole and Ugur Akpulat and Weiss, {Marjan M.} and Stephanie Efthymiou and Hanna, {Michael G.} and Carlo Minetti and Pasquale Striano and Livia Pisciotta and {De Grandis}, Elisa and Janine Altm{\"u}ller and Peter N{\"u}rnberg and Holger Thiele and Uluc Yis and Okur, {Tuncay Derya} and Polat, {Ayse Ipek} and Nafise Amiri and Mohammad Doosti and Karimani, {Ehsan Ghayoor} and Toosi, {Mehran B.} and Gabriel Haddad and Mert Karakaya and Brunhilde Wirth and {van Hagen}, {Johanna M.} and Wolf, {Nicole I.} and Reza Maroofian and Henry Houlden and Sebahattin Cirak and Gleeson, {Joseph G.}",
note = "Funding Information: The authors thank the subjects and their families for participating in this study. S.G. was sponsored by the Ruth L. Kirschstein Institutional National Research Service Award (T32 GM008666) from the National Institute on Deafness and Other Communication Disorders and by award F31HD095602 from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur) and the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel). We also thank Lisa Weixler for technical assistance and all the staff of the Cologne Center for Genomics for next-generation sequencing. The sequencing data were analyzed with the CHEOPS high-performace computer cluster of the Regional Computing Center of the University of Cologne. We thank DeCode for whole-genome sequencing. This work was supported by NIH grants R01NS048453 and R01NS052455, the Simons Foundation Autism Research Initiative, the Howard Hughes Medical Institute (to J.G.G.), the Deutsche Forschungsgemeinschaft Emmy Noether Programme (grant CI 218/1-1 to S.C.), the Wellcome Trust (WT093205MA and WT104033AIA), Ataxia UK, the UCL/UCLH NIHR Biomedical Research Centre, the Medical Research Council (to H.H. and M.H), EU Horizon 2020 Solve-RD, and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant 2012-305121 for the “Integrated European -omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)” to B.W. Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = sep,
day = "6",
doi = "10.1016/j.ajhg.2018.07.010",
language = "English",
volume = "103",
pages = "431--439",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",
}