PARP10 deficiency manifests by severe developmental delay and DNA repair defect.
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.
Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
Maher Awni
MA
Shahrour
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Claudia M
CM
Nicolae
Pediatric Neurology Unit, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.|Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Simon
S
Edvardson
Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
Motee
M
Ashhab
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Adri M
AM
Galvan
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Daniel
D
Constantin
Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
Bassam
B
Abu-Libdeh
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. gmoldovan@hmc.psu.edu.
George-Lucian
GL
Moldovan
Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. elpeleg@hadassah.org.il.
Orly
O
Elpeleg
D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002675:Child, Preschool; D004249:DNA Damage; D004260:DNA Repair; D002658:Developmental Disabilities / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000073359:Exome Sequencing
D011518:Proto-Oncogene Proteins; C499627:PARP10 protein, human; D011065:Poly(ADP-ribose) Polymerases
DNA repair; Neurodegeneration