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Targeted inversion and reversion of the blood coagulation factor 8 gene in human iPS cells using TALENs

Authors
 Chul-Yong Park  ;  Jungeun Kim  ;  Jiyeon Kweon  ;  Jeong Sang Son  ;  Jae Souk Lee  ;  Jeong-Eun Yoo  ;  Sung-Rae Chog  ;  Jong-Hoon Kim  ;  Jin-Soo Kim  ;  Dong-Wook Kim 
Citation
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.111(25) : 9253-9258, 2014 
Journal Title
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 
ISSN
 0027-8424 
Issue Date
2014
MeSH
Chromosome Inversion* ; Deoxyribonucleases/biosynthesis* ; Deoxyribonucleases/genetics ; Factor VIII/genetics* ; Factor VIII/metabolism ; Gene Targeting/methods* ; HEK293 Cells ; Hemophilia A*/genetics ; Hemophilia A*/metabolism ; Hemophilia A*/pathology ; Humans ; Induced Pluripotent Stem Cells/metabolism* ; Induced Pluripotent Stem Cells/pathology ; Models, Biological*
Keywords
CRISPR ; Cas9 ; ZFN ; genome editing
Abstract
Hemophilia A, one of the most common genetic bleeding disorders, is caused by various mutations in the blood coagulation factor VIII (F8) gene. Among the genotypes that result in hemophilia A, two different types of chromosomal inversions that involve a portion of the F8 gene are most frequent, accounting for almost half of all severe hemophilia A cases. In this study, we used a transcription activator-like effector nuclease (TALEN) pair to invert a 140-kbp chromosomal segment that spans the portion of the F8 gene in human induced pluripotent stem cells (iPSCs) to create a hemophilia A model cell line. In addition, we reverted the inverted segment back to its normal orientation in the hemophilia model iPSCs using the same TALEN pair. Importantly, we detected the F8 mRNA in cells derived from the reverted iPSCs lines, but not in those derived from the clones with the inverted segment. Thus, we showed that TALENs can be used both for creating disease models associated with chromosomal rearrangements in iPSCs and for correcting genetic defects caused by chromosomal inversions. This strategy provides an iPSC-based novel therapeutic option for the treatment of hemophilia A and other genetic diseases caused by chromosomal inversions.
Files in This Item:
T201401732.pdf Download
DOI
10.1073/pnas.1323941111
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Rehabilitation Medicine (재활의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Wook(김동욱) ORCID logo https://orcid.org/0000-0002-5025-1532
Park, Chul Yong(박철용) ORCID logo https://orcid.org/0000-0002-4467-9268
Cho, Sung-Rae(조성래) ORCID logo https://orcid.org/0000-0003-1429-2684
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/98911
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