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Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson\u2019s disease, amyotrophic lateral sclerosis, and Huntington\u2019s disease. Recessive <jats:italic>ADPRHL2\/<\/jats:italic>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 <jats:italic>ADPRHL2<\/jats:italic>. 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.<\/jats:p>","DOI":"10.26508\/lsa.202101057","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T22:35:14Z","timestamp":1630708514000},"page":"e202101057","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Biallelic <i>ADPRHL2<\/i> mutations in complex neuropathy affect ADP ribosylation and DNA damage response"],"prefix":"10.26508","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6593-7644","authenticated-orcid":true,"given":"Danique","family":"Beijer","sequence":"first","affiliation":[{"name":"Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium"},{"name":"Laboratory of Neuromuscular Pathology, Institute 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