Universität zu Köln

Kalasova, Ilona ORCID: 0000-0001-8235-1805, Hanzlikova, Hana ORCID: 0000-0001-7235-7269, Gupta, Neerja, Li, Yun, Altmueller, Janine, Reynolds, John J., Stewart, Grant S., Wollnik, Bernd, Yigit, Goekhan and Caldecott, Keith W. (2019). Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ. Neurol.-Genet., 5 (2). PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. 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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kalasova, Ilona UNSPECIFIED orcid.org/0000-0001-8235-1805 UNSPECIFIED Hanzlikova, Hana UNSPECIFIED orcid.org/0000-0001-7235-7269 UNSPECIFIED Gupta, Neerja UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Reynolds, John J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stewart, Grant S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Caldecott, Keith W. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-151279
DOI:	10.1212/NXG.0000000000000320
Journal or Publication Title:	Neurol.-Genet.
Volume:	5
Number:	2
Date:	2019
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	2376-7839
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language POLYNUCLEOTIDE KINASE; ATAXIA; SEIZURES Multiple languages Genetics & Heredity; Clinical Neurology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15127