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Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia

BACKGROUND: Fanconi anemia (FA) affects only one in 130,000 births, but has severe and diverse clinical consequences. It has been theorized that defects in the FA DNA cross‐link repair complex lead to a spectrum of variants that are responsible for those diverse clinical phenotypes. METHODS: Using N...

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Autores principales: Velmurugan, Karthik Raja, Michalak, Pawel, Kang, Lin, Fonville, Natalie C., Garner, Harold R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305641/
https://www.ncbi.nlm.nih.gov/pubmed/30450770
http://dx.doi.org/10.1002/mgg3.502
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author Velmurugan, Karthik Raja
Michalak, Pawel
Kang, Lin
Fonville, Natalie C.
Garner, Harold R.
author_facet Velmurugan, Karthik Raja
Michalak, Pawel
Kang, Lin
Fonville, Natalie C.
Garner, Harold R.
author_sort Velmurugan, Karthik Raja
collection PubMed
description BACKGROUND: Fanconi anemia (FA) affects only one in 130,000 births, but has severe and diverse clinical consequences. It has been theorized that defects in the FA DNA cross‐link repair complex lead to a spectrum of variants that are responsible for those diverse clinical phenotypes. METHODS: Using NextGen sequencing, we show that a clinically derived FA cell line had accumulated numerous genetic variants, including high‐impact mutations, such as deletion of start codons, introduction of premature stop codons, missense mutations, and INDELs. RESULTS: About 65% of SNPs and 55% of INDELs were found to be commonly present in both the FA dysfunctional and retrovirally corrected cell lines, showing their common origin. The number of INDELs, but not SNPs, is decreased in FANCD2‐corrected samples, suggesting that FANCD2 deficiency preferentially promotes the origin of INDELs. These genetic modifications had a considerable effect on the transcriptome, with statistically significant changes in the expression of 270 genes. These genetic and transcriptomic variants significantly impacted pathways and molecular functions, spanning a diverse spectrum of disease phenotypes/symptoms, consistent with the disease diversity seen in FA patients. CONCLUSION: These results underscore the consequences of defects in the DNA cross‐link repair mechanism and indicate that accumulating diverse mutations from individual parent cells may make it difficult to anticipate the longitudinal clinical behavior of emerging disease states in an individual with FA.
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spelling pubmed-63056412019-01-02 Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia Velmurugan, Karthik Raja Michalak, Pawel Kang, Lin Fonville, Natalie C. Garner, Harold R. Mol Genet Genomic Med Original Articles BACKGROUND: Fanconi anemia (FA) affects only one in 130,000 births, but has severe and diverse clinical consequences. It has been theorized that defects in the FA DNA cross‐link repair complex lead to a spectrum of variants that are responsible for those diverse clinical phenotypes. METHODS: Using NextGen sequencing, we show that a clinically derived FA cell line had accumulated numerous genetic variants, including high‐impact mutations, such as deletion of start codons, introduction of premature stop codons, missense mutations, and INDELs. RESULTS: About 65% of SNPs and 55% of INDELs were found to be commonly present in both the FA dysfunctional and retrovirally corrected cell lines, showing their common origin. The number of INDELs, but not SNPs, is decreased in FANCD2‐corrected samples, suggesting that FANCD2 deficiency preferentially promotes the origin of INDELs. These genetic modifications had a considerable effect on the transcriptome, with statistically significant changes in the expression of 270 genes. These genetic and transcriptomic variants significantly impacted pathways and molecular functions, spanning a diverse spectrum of disease phenotypes/symptoms, consistent with the disease diversity seen in FA patients. CONCLUSION: These results underscore the consequences of defects in the DNA cross‐link repair mechanism and indicate that accumulating diverse mutations from individual parent cells may make it difficult to anticipate the longitudinal clinical behavior of emerging disease states in an individual with FA. John Wiley and Sons Inc. 2018-11-18 /pmc/articles/PMC6305641/ /pubmed/30450770 http://dx.doi.org/10.1002/mgg3.502 Text en © 2018 Edward Via College of Osteopathic Medicine, VCOM Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Velmurugan, Karthik Raja
Michalak, Pawel
Kang, Lin
Fonville, Natalie C.
Garner, Harold R.
Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia
title Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia
title_full Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia
title_fullStr Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia
title_full_unstemmed Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia
title_short Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia
title_sort dysfunctional dna repair pathway via defective fancd2 gene engenders multifarious exomic and transcriptomic effects in fanconi anemia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305641/
https://www.ncbi.nlm.nih.gov/pubmed/30450770
http://dx.doi.org/10.1002/mgg3.502
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