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:
CreatorsEmailORCIDORCID Put Code
Kalasova, IlonaUNSPECIFIEDorcid.org/0000-0001-8235-1805UNSPECIFIED
Hanzlikova, HanaUNSPECIFIEDorcid.org/0000-0001-7235-7269UNSPECIFIED
Gupta, NeerjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reynolds, John J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stewart, Grant S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldecott, Keith W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
POLYNUCLEOTIDE KINASE; ATAXIA; SEIZURESMultiple languages
Genetics & Heredity; Clinical NeurologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15127

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