Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ
Citation Manager Formats
Make Comment
See Comments

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.
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. Sevil Yaşar and Dr. Behnam Sabayan
► Watch
Related Articles
- No related articles found.
Topics Discussed
Alert Me
Recommended articles
-
Article
Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutationsEnrico Bugiardini, Emanuela Bottani, Silvia Marchet et al.Neurology: Genetics, January 08, 2020 -
Clinical/Scientific Notes
Mutation in PNKP presenting initially as axonal Charcot-Marie-Tooth diseaseJosé Luiz Pedroso, Clarissa R.R. Rocha, Lucia I. Macedo-Souza et al.Neurology Genetics, October 22, 2015 -
Articles
Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathiesM. Lommel, S. Cirak, T. Willer et al.Neurology, January 11, 2010 -
Clinical/Scientific Notes
Expanding the ataxia with oculomotor apraxia type 4 phenotypeMartin Paucar, Helena Malmgren, Malcolm Taylor et al.Neurology Genetics, January 21, 2016