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Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ.
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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.
SUBMITTER: Kalasova I
PROVIDER: S-EPMC6454307 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ.
Neurology. Genetics 20190325 2
<h4>Objective</h4>To address the relationship between novel mutations in polynucleotide 5'-kinase 3'-phosphatase (PNKP), DNA strand break repair, and neurologic disease.<h4>Methods</h4>We have employed whole-exome sequencing, Sanger sequencing, and molecular/cellular biology.<h4>Results</h4>We describe here a patient with <i>microcephaly with early onset seizures</i> (MCSZ) from the Indian sub-continent harboring 2 novel mutations in <i>PNKP</i>, including a pathogenic mutation in the fork-head ...[more]