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

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...

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Detalles Bibliográficos
Autores principales: Kalasova, Ilona, Hanzlikova, Hana, Gupta, Neerja, Li, Yun, Altmüller, Janine, Reynolds, John J., Stewart, Grant S., Wollnik, Bernd, Yigit, Gökhan, Caldecott, Keith W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454307/
https://www.ncbi.nlm.nih.gov/pubmed/31041400
http://dx.doi.org/10.1212/NXG.0000000000000320
Descripción
Sumario: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.