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Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor. Sci Rep 2022 Mar 30;12(1):5386



Pubmed ID


Pubmed Central ID




Scopus ID

2-s2.0-85127252427 (requires institutional sign-in at Scopus site)   2 Citations


Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3'-phosphatase and DNA 5'-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinase/phosphatase activities, altered its cellular distribution, caused defective repair of DNA single/double stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.

Author List

Jiang B, Murray C, Cole BL, Glover JNM, Chan GK, Deschenes J, Mani RS, Subedi S, Nerva JD, Wang AC, Lockwood CM, Mefford HC, Leary SES, Ojemann JG, Weinfeld M, Ene CI


John D. Nerva MD Assistant Professor in the Neurosurgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Brain Neoplasms
Child, Preschool
DNA Repair
DNA Repair Enzymes
Phosphotransferases (Alcohol Group Acceptor)