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

Shereen G. Ghosh, Kerstin Becker, He Huang, Tracy Dixon-Salazar, Guoliang Chai, Vincenzo Salpietro, Lihadh Al-Gazali, Quinten Waisfisz, Haicui Wang, Keith K. Vaux, Valentina Stanley, Andreea Manole, Ugur Akpulat, Marjan M. Weiss, Stephanie Efthymiou, Michael G. Hanna, Carlo Minetti, Pasquale Striano, Livia Pisciotta, Elisa De GrandisJanine Altmüller, Peter Nürnberg, Holger Thiele, Uluc Yis, Tuncay Derya Okur, Ayse Ipek Polat, Nafise Amiri, Mohammad Doosti, Ehsan Ghayoor Karimani, Mehran B. Toosi, Gabriel Haddad, Mert Karakaya, Brunhilde Wirth, Johanna M. van Hagen, Nicole I. Wolf, Reza Maroofian, Henry Houlden, Sebahattin Cirak, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)431-439
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - Sept 6 2018


  • ADP-ribosylation
  • ARH3
  • ataxia
  • epilepsy
  • neurodegeneration
  • neuropathy
  • oxidative stress
  • poly-ADP ribose

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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