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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F19%3A00508188" target="_blank" >RIV/68378050:_____/19:00508188 - isvavai.cz</a>

Výsledek na webu

<a href="https://ng.neurology.org/content/5/2/e320" target="_blank" >https://ng.neurology.org/content/5/2/e320</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1212/NXG.0000000000000320" target="_blank" >10.1212/NXG.0000000000000320</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10601 - Cell biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

NEUROLOGY-GENETICS

ISSN

2376-7839

e-ISSN

—

Svazek periodika

5

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

7

Strana od-do

e320

Kód UT WoS článku

000481665200010

EID výsledku v databázi Scopus

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