Biallelic PARP1 Mutations Associated with Childhood-Onset Neurodegeneration

PARP1 is the primary human sensor protein for DNA single-strand breaks, reduced repair of which results in neurodevelopmental and/or progressive neurodegenerative disease typified by cerebellar ataxia, and oculomotor apraxia. Here, we report the first such disease associated with hereditary mutations in PARP1. The affected individual possesses biallelic mutations in the second DNA strand-break sensing zinc finger of PARP1, resulting in a predicted truncated protein of 127 amino acids that is comprised of just the first DNA strand-break sensing zinc finger. Levels of oxidative DNA damage-induced PARP activity are greatly reduced (~80%) in primary fibroblasts derived from the patient, when compared to cells derived from the parents, and levels of endogenous S-Phase PARP activity are reduced by >50%. Critically, whereas DNA double-strand break repair and cellular sensitivity to ionising radiation are largely normal in the patient-derived cells, the rate of repair of DNA single-strand breaks induced by either oxidative stress, during DNA base excision repair, or as a result of cytotoxic topoisomerase I activity is reduced. These data implicate hereditary mutations PARP1 in human hereditary neurodegenerative disease, and increase to five the number of DNA single-strand break repair genes associated with progressive cerebellar ataxia and oculomotor apraxia. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Medical Research Council ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Home Office Human Tissue Authority Licence 12119 & REC reference 19/WA/0091 (Health and Care Research Wales) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data present in the manuscript are available on reasonable request, following publication.