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Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ
journal contribution
posted on 2023-06-09, 17:27 authored by Ilona Kalasova, Hana Hanzlikova, Neerja Gupta, Yun Li, Janine Altmüller, John J Reynolds, Grant S Stewart, Bernd Wollnick, Gökhan Yigit, Keith CaldecottKeith CaldecottObjective: To address the relationship between novel mutations in polynucleotide 5'-kinase 3'-phosphatase (PNKP), DNA strand break repair, and neurologic disease. Methods: We have employed whole-exome sequencing, Sanger sequencing, and molecular/cellular biology. Results: We describe here a patient with microcephaly with early onset seizures (MCSZ) from the Indian sub-continent harboring 2 novel mutations in PNKP, including a pathogenic mutation in the fork-head associated domain. In addition, we confirm that MCSZ is associated with hyperactivation of the single-strand break sensor protein protein poly (ADP-ribose) polymerase 1 (PARP1) following the induction of abortive topoisomerase I activity, a source of DNA strand breakage associated previously with neurologic disease. Conclusions:These data expand the spectrum of PNKP mutations associated with MCSZ and show that PARP1 hyperactivation at unrepaired topoisomerase-induced DNA breaks is a molecular feature of this disease.
Funding
SIDSCA: Defective DNA Damage Responses in Dominant Neurodegenerative Diseases; G1930; EUROPEAN UNION; 694996
Cellular and Pathological Responses to Chromosomal DNA Single-Strand Breaks; G2053; MRC-MEDICAL RESEARCH COUNCIL; MR/P010121/1
History
Publication status
- Published
File Version
- Published version
Journal
Neurology GeneticsISSN
2376-7839Publisher
Lippincott, Williams & WilkinsExternal DOI
Issue
2Volume
5Page range
1-7Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes