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

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Item Type:Article
Title:Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ
Creators Name:Kalasova, I., Hanzlikova, H., Gupta, N., Li, Y., Altmüller, J., Reynolds, J.J., Stewart, G.S., Wollnik, B., Yigit, G. and Caldecott, K.W.
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.
Keywords:Genetics, Movement Disorders, Epilepsy/Seizures
Source:Neurology Genetics
ISSN:2376-7839
Publisher:American Academy of Neurology
Volume:5
Number:2
Page Range:e320
Date:April 2019
Official Publication:https://doi.org/10.1212/NXG.0000000000000320
PubMed:View item in PubMed

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