Gridina Maria, Orlova Polina, Serov Oleg
Genomic Mechanisms of Ontogenesis, Institute of Cytology and Genetics, Novosibirsk, Novosibirsk, Russia.
Ontogenetics, Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia.
PeerJ. 2025 Jan 20;13:e18567. doi: 10.7717/peerj.18567. eCollection 2025.
Copy number variations of the human gene, resulting from megabase-scale microdeletions or microduplications in the 3p26.3 region, are frequently implicated in neurodevelopmental disorders such as intellectual disability and developmental delay. However, duplication of the full-length human gene presents with variable penetrance, resulting in phenotypes that range from neurodevelopmental disorders to no visible pathologies, even within the same family. Previously, we obtained a set of induced pluripotent stem cell lines derived from a patient with a gene duplication and from two healthy donors. Our findings demonstrated that expression in neurons carrying the duplication was significantly reduced. Additionally, the expression from the duplicated allele was markedly lower compared to the wild-type allele. Here, we first introduce a system for correcting megabase-scale duplications in induced pluripotent stem cells and secondly analyze the impact of this correction on gene expression. We showed that the deletion of one copy of the duplication did not affect the expression levels of the remaining allele in the neuronal cells.
人类基因的拷贝数变异，源于3p26.3区域的兆碱基规模的微缺失或微重复，常与神经发育障碍如智力残疾和发育迟缓有关。然而，全长人类基因的重复表现出可变的外显率，导致从神经发育障碍到无可见病理表现的各种表型，即使在同一家族中也是如此。此前，我们从一名患有该基因重复的患者和两名健康供体中获得了一组诱导多能干细胞系。我们的研究结果表明，携带该重复的神经元中的该基因表达显著降低。此外，与野生型等位基因相比，重复等位基因的表达明显更低。在此，我们首先介绍一种用于纠正诱导多能干细胞中兆碱基规模重复的系统，其次分析这种纠正对该基因表达的影响。我们表明，删除该重复的一个拷贝不会影响神经元细胞中其余等位基因的表达水平。
