Abstract
Chromosomal segregation errors in germ cells and early embryonic development underlie aneuploidies, which are numerical chromosomal abnormalities causing fetal absorption, developmental anomalies, and carcinogenesis. It has been considered that human aneuploidy disorders cannot be resolved by radical treatment. However, recent studies have demonstrated that aneuploidies can be rescued to a normal diploid state using genetic engineering in cultured cells. Here, we summarize a series of studies mainly applying genome editing to eliminate an extra copy of human chromosome 21, the cause of the most common constitutional aneuploidy disorder Down syndrome. We also present findings on induced pluripotent stem cell reprogramming, which has been shown to be one of the most promising technologies for converting aneuploidies into normal diploidy without the risk of genetic alterations such as genome editing-mediated off-target effects.
Highlights
Matsumura et al [85] applied a chromosome elimination cassette (CEC), featuring fluorescent-protein and puromycin resistance genes surrounded by inverted loxP sites into chromosome deletions in cultured cells in vitro
A cassette of green fluorescent protein (GFP) and herpes simplex virus-thymidine kinase (HSV-tk) genes surrounded by inverted loxP sites was integrated into one copy of chromosome 21 in the trisomy HeLa cells by homologous recombination following CRISPR/Cas9 system-mediated
Introduction of a gene cassette for positive and negative drug selection into one copy of chromosome 21 via a conventional gene-targeting method demonstrated the correction of trisomy to disomy in Down syndrome (DS) patient-derived induced pluripotent stem cells
Summary
Eukaryotic cells have developed a surveillance mechanism to ensure accurate chromosomal segregation during cell division. Errors during meiosis or mitosis can generate daughter cells with an abnormal number of chromosomes, a phenomenon called “aneuploidy” (i.e., not euploidy). Aneuploid cells exhibit gain or loss of a whole chromosome, causing abnormalities in embryonic development and a predisposition to cancer [1,2,3]. The risk of embryonic aneuploidies leading to miscarriage or congenital disorders generally increases with maternal age [4,5,6,7]. Monosomies (possessing only one chromosome of a pair) are basically deleterious due to the level of gene expression being insufficient for cell survival; most such cases, except for monosomy X, are embryonically lethal [13].
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