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.