Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements
Abstract: CRISPR-based genome editing of pseudogene-associated disorders, such as p47phox-deficient chronic granulomatous disease (p47 CGD), is challenged by chromosomal rearrangements due to presence of multiple targets. We report that interactions between highly homologous sequences that are localized on the same chromosome contribute substantially to post-editing chromosomal rearrangements. We successfully employed editing approaches at the NCF1 gene and its pseudogenes, NCF1B and NCF1C, in a human cell line model of p47 CGD and in patient-derived human hematopoietic stem and progenitor cells. Upon genetic engineering, a droplet digital PCR-based method identified cells with altered copy numbers, spanning megabases from the edited loci. We attributed the high aberration frequency to the interaction between repetitive sequences and their predisposition to recombination events. Our findings emphasize the need for careful evaluation of the target-specific genomic context, such as the presence of homologous regions, whose instability can constitute a risk factor for chromosomal rearrangements upon genome editing
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Communications biology. - 7, 1 (2024) , 1291, ISSN: 2399-3642
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
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Universität
- (when)
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2024
- Creator
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Raimondi, Federica
Siow, Kah Mun
Wrona, Dominik
Fuster García, Carla
Pastukhov, Oleksandr
Schmitz, Lienhard
Bargsten, Katja
Kissling, Lucas
Swarts, Daan C.
Geoffroy, Andrieux
Cathomen, Anton
Modlich, Ute
Jínek, Martin
Siler, Ulrich
Reichenbach, Janine
- DOI
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10.1038/s42003-024-06959-z
- URN
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urn:nbn:de:bsz:25-freidok-2576304
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:36 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Raimondi, Federica
- Siow, Kah Mun
- Wrona, Dominik
- Fuster García, Carla
- Pastukhov, Oleksandr
- Schmitz, Lienhard
- Bargsten, Katja
- Kissling, Lucas
- Swarts, Daan C.
- Geoffroy, Andrieux
- Cathomen, Anton
- Modlich, Ute
- Jínek, Martin
- Siler, Ulrich
- Reichenbach, Janine
- Universität
Time of origin
- 2024
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Establishing a zinc finger nuclease platform for targeted genome editing in human cell lines, primary keratinocyte stem cells and cardiomyocytes in vivo
Entwicklung von gentechnologischen Strategien zur Überwindung der Bluthirnschranke am Modell des Morbus Gaucher Typ 2
CRISPR/Cas9 - einschneidende Revolution in der Gentechnik
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Natural history of Pearson syndrome