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

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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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

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Project NameSussex Project NumberFunderFunder Ref
SIDSCA: Defective DNA Damage Responses in Dominant Neurodegenerative DiseasesG1930EUROPEAN UNION694996
Cellular and Pathological Responses to Chromosomal DNA Single-Strand BreaksG2053MRC-MEDICAL RESEARCH COUNCILMR/P010121/1