Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ

Ilona Kalasova, Hana Hanzlikova, Neerja Gupta, Yun Li, Janine Altmüller, John J Reynolds, Grant S Stewart, Bernd Wollnik, Gökhan Yigit, Keith W Caldecott

Research output: Contribution to journalArticlepeer-review


OBJECTIVE: 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.

Original languageEnglish
Article numbere320
Number of pages9
JournalNeurology Genetics
Issue number2
Early online date5 Mar 2019
Publication statusPublished - Apr 2019

Bibliographical note

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Funding & Acknowledgements: The Article Processing Charge was funded by the ERC. This work was funded by an ERC advanced investigator award to KWC (SIDSCA; 694996). Access to the Olympus ScanR and Leica microscope at the Light Microscopy Core Facility, IMG CAS, Prague was supported by MEYS (LM2015062), OPPK (CZ.2.16/3.1.00/21547), and NPU the authors (LO1419). This work used instruments provided by C4Sys infrastructure. GSS is funded by a CR-UK programme grant (C17183/A23303) and JJR is funded by the University of Birmingham.


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