Title: PARP10 deficiency manifests by severe developmental delay and DNA repair defect.

Authors: Shahrour, Maher Awni; Nicolae, Claudia M; Edvardson, Simon; Ashhab, Motee; Galvan, Adri M; Constantin, Daniel; Abu-Libdeh, Bassam; Moldovan, George-Lucian; Elpeleg, Orly

Published In Neurogenetics, (2016 Oct)

Abstract: DNA repair mechanisms such as nucleotide excision repair (NER) and translesion synthesis (TLS) are dependent on proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory protein. Recently, homozygosity for p.Ser228Ile mutation in the PCNA gene was reported in patients with neurodegeneration and impaired NER. Using exome sequencing, we identified a homozygous deleterious mutation, c.648delAG, in the PARP10 gene, in a patient suffering from severe developmental delay. In agreement, PARP10 protein was absent from the patient cells. We have previously shown that PARP10 is recruited by PCNA to DNA damage sites and is required for DNA damage resistance. The patient cells were significantly more sensitive to hydroxyurea and UV-induced DNA damage than control cells, resulting in increased apoptosis, indicating DNA repair impairment in the patient cells. PARP10 deficiency joins the long list of DNA repair defects associated with neurodegenerative disorders, including ataxia telangiectasia, xeroderma pigmentosum, Cockayne syndrome, and the recently reported PCNA mutation.

PubMed ID: 27624574

MeSH Terms: Brain/diagnostic imaging; Brain/pathology; Child, Preschool; DNA Damage*; DNA Repair*; Developmental Disabilities/diagnostic imaging; Developmental Disabilities/genetics*; Developmental Disabilities/pathology; Exome Sequencing; Homozygote; Humans; Magnetic Resonance Imaging; Male; Mutation; Pedigree; Poly(ADP-ribose) Polymerases/genetics*; Proto-Oncogene Proteins/genetics*