Kalasova, Ilona, Hanzlikova, Hana, Gupta, Neerja, Li, Yun, Altmüller, Janine, Reynolds, John J, Stewart, Grant S, Wollnick, Bernd, Yigit, Gökhan and Caldecott, Keith W (2019) Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ. Neurology Genetics, 5 (2). pp. 1-7. ISSN 2376-7839

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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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups:	Genome Damage and Stability Centre
Subjects:	Q Science > Q Science (General)
Depositing User:	Paula Amiet-West
Date Deposited:	07 May 2019 10:13
Last Modified:	01 Jul 2019 15:45
URI:	http://sro.sussex.ac.uk/id/eprint/82956

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