Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 103, Issue 3, Pages 431-439Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2018.07.010
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Funding
- Ruth L. Kirschstein Institutional National Research Service Award from the National Institute on Deafness and Other Communica-tion Disorders [T32 GM008666]
- Ruth L. Kirschstein Institutional National Research Service Award from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development [F31HD095602]
- Broad Institute [U54HG003067, UM1HG008900]
- Yale Center for Mendelian Disorders [U54HG006504]
- NIH [R01NS048453, R01NS052455]
- Simons Foundation Autism Research Initiative
- Howard Hughes Medical Institute
- Deutsche Forschungsgemeinschaft Emmy Noether Programme [CI 218/1-1]
- Wellcome Trust [WT093205MA, WT104033AIA]
- Ataxia UK
- UCL/UCLH NIHR Biomedical Research Centre
- Medical Research Council
- EU Horizon 2020 Solve-RD
- European Community's Seventh Framework Programme (FP7/2007-2013) [2012-305121]
- MRC [G0601943, MR/K000608/1] Funding Source: UKRI
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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.
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