Since it is extremely difficult to establish an animal model for human chromosomal abnormalities, induced pluripotent stem cells (iPSCs) provide a powerful alternative to study underlying mechanisms of these disorders and identify potential therapeutic interventions. In this study we established iPSCs from a young girl with a hemizygous deletion of Xq27.3-q28 who exhibited global developmental delay and intellectual disability from early in infancy. The deletion site on the X chromosome includes Fragile X Mental Retardation 1 (FMR1), the gene responsible for fragile X syndrome, which likely contributes to the patient's neurodevelopmental abnormalities. The FMR1 gene was expressed in approximately half of the iPSC clones we generated while it was absent in the other half due to the random inactivation of normal and abnormal X chromosomes. The normal or absent expression pattern of the FMR1 gene was not altered when the iPSCs were differentiated into neural progenitor cells (NPCs). Moreover, chromosome reactivating reagents such as 5-aza-2-deoxycytidine, trichostatin A, and UNC0638, were tested in an attempt to reactivate the suppressed FMR1 gene in affected iPSC-NPCs. The affected and control isogenic iPSCs developed in this study are ideal models with which to identify downstream consequences caused by the Xq27.3-q28 deletion and also to provide tools for high-throughput screening to identify compounds potentially improving the well-being of this patient population.

中文翻译：

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从 Xq27.3-q28 缺失的女性患者中产生诱导多能干细胞以建立疾病模型和确定治疗方法。

由于建立人类染色体异常的动物模型极其困难，因此诱导多能干细胞 (iPSC) 为研究这些疾病的潜在机制和确定潜在的治疗干预措施提供了强有力的替代方案。在这项研究中，我们从一名 Xq27.3-q28 半合子缺失的年轻女孩身上建立了 iPSC，该女孩从婴儿早期就表现出全球发育迟缓和智力障碍。X 染色体上的缺失位点包括脆性 X 智力低下 1 (FMR1)，这是导致脆性 X 综合征的基因，这可能导致患者的神经发育异常。FMR1 基因在我们生成的大约一半 iPSC 克隆中表达，而另一半由于正常和异常 X 染色体的随机失活而缺失。当 iPSC 分化为神经祖细胞 (NPC) 时，FMR1 基因的正常或缺失表达模式没有改变。此外，还测试了染色体激活试剂，例如 5-aza-2-deoxycytidine、曲古抑菌素 A 和 UNC0638，试图重新激活受影响 iPSC-NPC 中抑制的 FMR1 基因。本研究中开发的受影响和对照同基因 iPSC 是理想的模型，可用于识别由 Xq27.3-q28 缺失引起的下游后果，并为高通量筛选提供工具，以识别可能改善该患者福祉的化合物人口。测试了曲古抑菌素 A 和 UNC0638，试图重新激活受影响的 iPSC-NPC 中抑制的 FMR1 基因。本研究中开发的受影响和对照同基因 iPSC 是理想的模型，可用于识别由 Xq27.3-q28 缺失引起的下游后果，并为高通量筛选提供工具，以识别可能改善该患者福祉的化合物人口。测试了曲古抑菌素 A 和 UNC0638，试图重新激活受影响的 iPSC-NPC 中抑制的 FMR1 基因。本研究中开发的受影响和对照同基因 iPSC 是理想的模型，可用于识别由 Xq27.3-q28 缺失引起的下游后果，并为高通量筛选提供工具，以识别可能改善该患者福祉的化合物人口。