Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini 1, 71013 San Giovanni Rotondo, Foggia, Italy.
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Viale Abramo Lincoln 5, 81100 Caserta, Italy.
Int J Mol Sci. 2020 Mar 9;21(5):1860. doi: 10.3390/ijms21051860.
Recent cutting-edge human genetics technology has allowed us to identify copy number variations (CNVs) and has provided new insights for understanding causative mechanisms of human diseases. A growing number of studies show that CNVs could be associated with physiological mechanisms linked to evolutionary trigger, as well as to the pathogenesis of various diseases, including cancer, autoimmune disease and mental disorders such as autism spectrum disorders, schizophrenia, intellectual disabilities or attention-deficit/hyperactivity disorder. Their incomplete penetrance and variable expressivity make diagnosis difficult and hinder comprehension of the mechanistic bases of these disorders. Additional elements such as co-presence of other CNVs, genomic background and environmental factors are involved in determining the final phenotype associated with a CNV. Genetically engineered animal models are helpful tools for understanding the behavioral consequences of CNVs. However, the genetic background and the biology of these animal model systems have sometimes led to confusing results. New cellular models obtained through somatic cellular reprogramming technology that produce induced pluripotent stem cells (iPSCs) from human subjects are being used to explore the mechanisms involved in the pathogenic consequences of CNVs. Considering the vast quantity of CNVs found in the human genome, we intend to focus on reviewing the current literature on the use of iPSCs carrying CNVs on chromosome 15, highlighting advantages and limits of this system with respect to mouse model systems.
最近的前沿人类遗传学技术使我们能够识别拷贝数变异 (CNVs)，并为理解人类疾病的致病机制提供了新的见解。越来越多的研究表明，CNVs 可能与进化触发相关的生理机制以及各种疾病的发病机制有关，包括癌症、自身免疫性疾病和精神障碍，如自闭症谱系障碍、精神分裂症、智力障碍或注意缺陷多动障碍。它们不完全外显和可变表达使得诊断变得困难，并阻碍了对这些疾病的机制基础的理解。其他因素，如其他 CNVs 的共存、基因组背景和环境因素，都参与决定与 CNV 相关的最终表型。基因工程动物模型是理解 CNVs 行为后果的有用工具。然而，这些动物模型系统的遗传背景和生物学特性有时会导致令人困惑的结果。通过体细胞核重编程技术获得的新的细胞模型可以产生诱导多能干细胞 (iPSCs)，这些细胞模型来自人类受试者，用于探索 CNVs 致病后果所涉及的机制。考虑到人类基因组中发现的大量 CNVs，我们打算重点回顾关于携带 15 号染色体 CNVs 的 iPSCs 的当前文献，强调该系统相对于小鼠模型系统的优势和限制。
