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

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posted on 2023-06-09, 17:27 authored by Ilona Kalasova, Hana Hanzlikova, Neerja Gupta, Yun Li, Janine Altmüller, John J Reynolds, Grant S Stewart, Bernd Wollnick, Gökhan Yigit, Keith CaldecottKeith Caldecott
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.

Funding

SIDSCA: Defective DNA Damage Responses in Dominant Neurodegenerative Diseases; G1930; EUROPEAN UNION; 694996

Cellular and Pathological Responses to Chromosomal DNA Single-Strand Breaks; G2053; MRC-MEDICAL RESEARCH COUNCIL; MR/P010121/1

History

Publication status

  • Published

File Version

  • Published version

Journal

Neurology Genetics

ISSN

2376-7839

Publisher

Lippincott, Williams & Wilkins

Issue

2

Volume

5

Page range

1-7

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-05-07

First Open Access (FOA) Date

2019-05-07

First Compliant Deposit (FCD) Date

2019-05-07

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