%0 Journal Article
%T Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome
%A Andreea Manole
%A Ayse Ipek Polat
%A Brunhilde Wirth
%A Carlo Minetti
%A Ehsan Ghayoor Karimani
%A Elisa De Grandis
%A Gabriel Haddad
%A Guoliang Chai
%A Haicui Wang
%A He Huang
%A Henry Houlden
%A Holger Thiele
%A Janine Altmščller
%A Johanna M. van Hagen
%A Keith K. Vaux
%A Kerstin Becker
%A Lihadh Al-Gazali
%A Livia Pisciotta
%A Marjan M. Weiss
%A Mehran B. Toosi
%A Mert Karakaya
%A Michael G. Hanna
%A Mohammad Doosti
%A Nafise Amiri
%A Nicole I. Wolf
%A Pasquale Striano
%A Peter Nščrnberg
%A Quinten Waisfisz
%A Reza Maroofian
%A Sebahattin Cirak
%A Shereen G. Ghosh
%A Stephanie Efthymiou
%A Tracy D. Salazar
%A Tuncay Derya Okur
%A Ugur Akpulat
%A Uluc Yis
%A Valentina Stanley
%A Vincenzo Salpietro
%J Archive of "American Journal of Human Genetics".
%D 2018
%R 10.1016/j.ajhg.2018.07.010
%X 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
%K ADPRHL2
%K ARH3
%K ADP-ribosylation
%K poly-ADP ribose
%K oxidative stress
%K neurodegeneration
%K epilepsy
%K ataxia
%K neuropathy
%K SUDEP
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128219/