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April 2019; 5 (2) ArticleOpen Access

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

Ilona Kalasova, Hana Hanzlikova, Neerja Gupta, Yun Li, Janine Altmüller, John J. Reynolds, Grant S. Stewart, Bernd Wollnik, Gökhan Yigit, Keith W. Caldecott
First published March 25, 2019, DOI: https://doi.org/10.1212/NXG.0000000000000320
Ilona Kalasova
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Hana Hanzlikova
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Neerja Gupta
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Yun Li
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Janine Altmüller
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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John J. Reynolds
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Grant S. Stewart
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Bernd Wollnik
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Gökhan Yigit
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Keith W. Caldecott
From the Department of Genome Dynamics (I.K., H.H., K.W.C.), Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Republic; Genome Damage and Stability Centre (H.H., K.W.C.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK; Institute of Human Genetics (Y.L., B.W., G.Y.), University Medical Center Göttingen, Germany; Cologne Center for Genomics (J.A.), University of Cologne, Germany; Institute of Cancer and Genomic Sciences (J.J.R., G.S.S.), College of Medical and Dental Sciences, University of Birmingham, UK; and Division of Genetics (N.G.), Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Citation
Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ
Ilona Kalasova, Hana Hanzlikova, Neerja Gupta, Yun Li, Janine Altmüller, John J. Reynolds, Grant S. Stewart, Bernd Wollnik, Gökhan Yigit, Keith W. Caldecott
Neurol Genet Apr 2019, 5 (2) e320; DOI: 10.1212/NXG.0000000000000320

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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.

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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