2. Academic Validation
  3. Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response

Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response

  • Life Sci Alliance. 2021 Sep 3;4(11):e202101057. doi: 10.26508/lsa.202101057.
Danique Beijer 1 2,  Thomas Agnew 3,  Johannes Gregor Matthias Rack 3,  Evgeniia Prokhorova 3,  Tine Deconinck 1 2,  Berten Ceulemans 4,  Stojan Peric 5,  Vedrana Milic Rasic 6,  Peter De Jonghe 1 2 7,  Ivan Ahel 8,  Jonathan Baets 9 2 7
Affiliations

Affiliations

  • 1 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
  • 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 3 Sir William Dunn School of Pathology, Oxford University, Oxford, UK.
  • 4 Department of Pediatric Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • 5 Neurology Clinic, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
  • 6 Clinic for Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
  • 7 Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • 8 Sir William Dunn School of Pathology, Oxford University, Oxford, UK ivan.ahel@path.ox.ac.uk.
  • 9 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium Jonathan.Baets@uantwerpen.be.
PMID: 34479984 DOI: 10.26508/lsa.202101057
Abstract

ADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.g., ARH3 and PARG), ensuring synthesis and removal of mono-ADP-ribose or poly-ADP-ribose chains on protein substrates. Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Recessive ADPRHL2/ARH3 mutations are described to cause a stress-induced epileptic ataxia syndrome with developmental delay and axonal neuropathy (CONDSIAS). Here, we present two families with a neuropathy predominant disorder and homozygous mutations in ADPRHL2 We characterized a novel C26F mutation, demonstrating protein instability and reduced protein function. Characterization of the recurrent V335G mutant demonstrated mild loss of expression with retained enzymatic activity. Although the V335G mutation retains its mitochondrial localization, it has altered cytosolic/nuclear localization. This minimally affects basal ADP ribosylation but results in elevated nuclear ADP ribosylation during stress, demonstrating the vital role of ADP ribosylation reversal by ARH3 in DNA damage control.

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