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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. and Hanzlikova, H. and Gupta, N. and Li, Y. and Altmüller, J. and Reynolds, J.J. and Stewart, G.S. and Wollnik, B. and 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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