Abstract
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.
Glossary
- CCG=
- Cologne Center for Genomics;
- CPT=
- camptothecin;
- FHA=
- fork-head associated;
- HRP=
- horseradish peroxidase;
- MCSZ=
- microcephaly with early onset seizures;
- PARP1=
- protein poly (ADP-ribose) polymerase 1;
- PNKP=
- polynucleotide 5′-kinase 3′-phosphatase;
- SCAN-1=
- spinocerebellar ataxia with axonal neuropathy-1;
- SSBR=
- single-strand break repair;
- WES=
- whole-exome sequencing
Footnotes
↵* These authors contributed equally.
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
The Article Processing Charge was funded by the ERC.
- Received November 6, 2018.
- Accepted in final form February 7, 2019.
- 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.
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