Applications of Genome Editing Technology in Research on Chromosome Aneuploidy Disorders
Abstract
:1. Introduction
1.1. Human Genetic Aneuploidy Disorders
1.2. Autosomal Chromosomes
1.2.1. Trisomy 21 (Down Syndrome)
1.2.2. Trisomy 18 (Edwards Syndrome)
1.2.3. Trisomy 13 (Patau Syndrome)
1.3. Sex Chromosomes
1.3.1. Turner Syndrome (45,X)
1.3.2. Klinefelter Syndrome
1.4. Mosaic Variegated Aneuploidy (MVA)
1.4.1. MVA1 or MVA1 Syndrome
1.4.2. MVA2
1.4.3. MVA3
2. Gene Targeting-Mediated Chromosome Elimination
2.1. Cre/loxP System-Mediated Chromosome Elimination
2.2. Conventional Gene-Targeting Mediated Dual Drug Selection Cassette Knock-In
2.3. Genome Editing Technology for Rescuing Trisomy In Vitro and In Vivo
2.3.1. Zinc Finger Nuclease (ZFN) Mediated the XIST Gene Knock-In to Silence an Extra Chromosome 21 in Down Syndrome Patient Cells
2.3.2. CRISPR/Cas9 System to Introduce Multiple DNA Cleavages for Target Chromosome Elimination
3. Reprogramming-Mediated Karyotype Correction
3.1. Cell-Autonomous Correction of Ring Chromosome During iPSC Reprogramming
3.2. Trisomy-Biased Chromosome Loss (TCL) to Convert the Trisomy into Disomy During iPSC Reprogramming
4. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Disease | Inheritance | Causative Gene (Gene Ontology) | Chromosome Imbalance | Frequency of Patients | Clinical Features | ||||
---|---|---|---|---|---|---|---|---|---|
Congenital Heart Defect | Microcephaly | Mental Retardation | Cancer Predisposition | Others | |||||
Autosomal chromosome | |||||||||
Down syndrome | IC | T 21 | 1/750 live births | + | − | + | + | upward-slanting palpebral fissures, epicanthal folds, single palm fold | |
Edwards syndrome | IC | T 18 | 1/6000–1/8000 live births | + | + | unknown | unknown | prominent occiput, low-set malformed ear, micrognathia | |
Patau syndrome | IC | T 13 | 1/20,000 live births | + | + | unknown | unknown | polydactyl, midline cleft lip, flexion of the fingers, polycystic kidneys | |
Mosaic trisomy 8 | IC | Mosaic T 8 | >100 cases reported | + | − | + | + | morphological brain abnormalities, high arched or cleft palate, micrognathia, renal malformation | |
Mosaic trisomy 9 | IC | Mosaic T 9 | >40 cases reported | + | − | + | + | morphological brain abnormalities, micrognathia, Dandy–Walker malformation, renal malformation | |
Mosaic trisomy 22 | IC | Mosaic T 22 | >20 cases reported | + | + | + | unknown | hemi dystrophy, midfacial hypoplasia, cleft palate, micrognathia, renal hypoplasia | |
Sex chromosome | |||||||||
Turner syndrome | IC | M X | 1/2000–1/5000 live female births | + | + | + | − | posteriorly rotated ears, neck webbing, broad chest, short stature, micrognathia | |
Klinefelter syndrome | IC | add chr X in male | 1/426–1/1000 live male births | − | − | + | − | tall stature, long limbs, hypogonadism, infertility | |
XXX syndrome | IC | T X | 1/900 live female births | − | − | − | − | tall stature, normal fertility | |
XYY syndrome | IC | add chr Y in male | 1/800–1/1000 live male births | − | − | − | − | tall stature, hyperactive behavior, distractibility, temper tantrums, low frustration tolerance | |
Mosaic Variegated Aneuploidy (MVA)—autosomal and sex chromosome | |||||||||
MVA1 or MVA | AR | BUB1B (mitotic SAC) | M, T, and double T | <1/1,000,000 live births | + | + | + | + | Dandy–Walker complex, cataracts, premature aging, multiple renal cysts |
MVA2 | AR | Cep57 (spindle pole integrity) | M, T, and double T | 5 cases reported | + | + | + | − | rhizomelic shortening of the upper limbs, skull anomalies |
MVA3 | AR | TRIP13 (mitotic SAC) | M, T, and double T | 6 cases reported | − | − | + | + | seizures, abnormal skin pigmentation, arthrogryposis |
Used Genome Editing System | Aneuploidy Focused | Purpose | Cell Type | Target Gene Locus | Transgene | Selection Method | Initial → Final Genotype | Reference |
---|---|---|---|---|---|---|---|---|
Cre/inverted loxP | XY genotype | Chr del | Mouse zygotes | chr Y | Y-inverted loxP transgene | − | XY → XO | [83] |
Tetraploid mESC | Chr del | mES somatic hybrid cells | chr 11, chr 12, chr 6 | CEC | Puro drug selection, sorting by FACS | 40,XY (2n) → 80,XXYY (4n)→ 79,XXYY (4n) | [85] | |
Tetraploid mESC | Chr del | Hybrid cells from two CEC transgenic ESC lines (CEC-ESC) | chr 6, chr 11, chr 12, chr 17 | CEC | Puro and neo drug selection, sorting by FACS | 80,XXXY (4n) → 78,XXYY (4n) | [84] | |
CEC-mESC | Chr del | Transgenic mESC containing a copy of CEC (CEC-ESC) | chr 5 (band F), chr 13 (band A) | CEC | Sorting by FACS | 40,XY → 39,XY | [80] | |
Down syndrome | Chr del | HeLa cells with three copies of chr 21 | intergenic region between RCAN1 and CLIC6 genes | loxP-HSV-tk | GCV drug selection | 47,+21 → 46 | [82] | |
Tetraploid MEF | Chr del | Tetraploid immortalized murine embryonic fibroblasts | chr 9, chr 10, chr 12, chr 14 | GFP-inverted loxP-hDC2 | Sorting by FACS | 40,XY (2n) → 80,XXYY (4n) → 79,XXYY (4n) | [79] | |
Conventional gene targeting | Down syndrome | Knock-in | Down syndrome hiPSC | APP gene | TKNEO | Neo and GCV drug selection | 47,+21 → 46 | [86] |
ZFNs | Down syndrome | Silencing the chr 21 | Down syndrome hiPSC | DYRK1A gene | XIST | Puro drug selection | 47,+21 → 47,+21(chr Barr) | [89] |
CRISPR/Cas9 | XY genotype | Chr del | mESCs | SRE of centromere and long arm of chr Y | − | Puro drug selection | XY → XO | [88] |
XY genotype | Chr del | mESCs | SRE of Rbmy1a1 and Ssty2 genes | − | Sorting by FACS | XY → XO | [87] | |
XY genotype | Chr del | Mouse brain | SRE of Rbmy1a1 and Ssty2 genes | − | Sorting by FACS | XY → XO | [87] | |
Turner syndrome | Chr del | Mouse zygotes | SRE of Rbmy1a1, Ssty1, and Ssty2 genes | − | − | XY → XO | [87] | |
Turner syndrome | Chr del | Mouse zygotes | SRE of long arm of chr X | − | − | XX → XO | [87] | |
mESC aneuploidy | Chr del | Stable mESC line with an extra human chr 14 established by chr transfer | SRE of long arm of chr 14 | − | Sorting by FACS | mChr14 = 1 → mChr14 = 0 | [87] | |
Down syndrome | Chr del | mESCs with trisomy 21/hiPSCs with trisomy 21 | SRE of long arm of chr 21 | − | Sorting by FACS | 47,+21 → 46 | [87] | |
Cancer | Chr del | Human cancer cell line HT-29 | SRE of short and long arm of chr 7 | − | Sorting by FACS | hChr7 = 4 →hChr7 = 3 | [87] |
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Akutsu, S.N.; Fujita, K.; Tomioka, K.; Miyamoto, T.; Matsuura, S. Applications of Genome Editing Technology in Research on Chromosome Aneuploidy Disorders. Cells 2020, 9, 239. https://doi.org/10.3390/cells9010239
Akutsu SN, Fujita K, Tomioka K, Miyamoto T, Matsuura S. Applications of Genome Editing Technology in Research on Chromosome Aneuploidy Disorders. Cells. 2020; 9(1):239. https://doi.org/10.3390/cells9010239
Chicago/Turabian StyleAkutsu, Silvia Natsuko, Kazumasa Fujita, Keita Tomioka, Tatsuo Miyamoto, and Shinya Matsuura. 2020. "Applications of Genome Editing Technology in Research on Chromosome Aneuploidy Disorders" Cells 9, no. 1: 239. https://doi.org/10.3390/cells9010239
APA StyleAkutsu, S. N., Fujita, K., Tomioka, K., Miyamoto, T., & Matsuura, S. (2020). Applications of Genome Editing Technology in Research on Chromosome Aneuploidy Disorders. Cells, 9(1), 239. https://doi.org/10.3390/cells9010239