Copy number variants (CNVs) linked to genes involved in nervous system development or function are often associated with neuropsychiatric disease. While CNVs involving deletions generally cause severe and highly penetrant patient phenotypes, CNVs leading to duplications tend instead to exhibit widely variable and less penetrant phenotypic expressivity among affected individuals. CNVs located on chromosome 15q13.3 affecting the alpha-7 nicotinic acetylcholine receptor subunit (CHRNA7) gene contribute to multiple neuropsychiatric disorders with highly variable penetrance. However, the basis of such differential penetrance remains uncharacterized. Here, we generated induced pluripotent stem cell (iPSC) models from first-degree relatives with a 15q13.3 duplication and analyzed their cellular phenotypes to uncover a basis for the dissimilar phenotypic expressivity. The first-degree relatives studied included a boy with autism and emotional dysregulation (the affected proband-AP) and his clinically unaffected mother (UM), with comparison to unrelated control models lacking this duplication. Potential contributors to neuropsychiatric impairment were modeled in iPSC-derived cortical excitatory and inhibitory neurons. The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or unrelated controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and Wnt, axonal guidance, and GABA receptor signaling. The UM model instead exhibited upregulated expression of genes in many of these same pathways, suggesting that molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in this model. However, both AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity. These data define both diagnosis-associated cellular phenotypes and shared functional anomalies related to CHRNA7 duplication that may contribute to variable phenotypic penetrance in individuals with 15q13.3 duplication. The capacity for pharmacological agents to rescue some neurodevelopmental anomalies associated with diagnosis suggests avenues for intervention for carriers of this duplication and other CNVs that cause related disorders.

中文翻译：

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与涉及 CHRNA7 的常见 15 号染色体重复相关的神经元生理学、发育和功能的改变


与神经系统发育或功能相关的基因相关的拷贝数变异（CNV）通常与神经精神疾病有关。虽然涉及缺失的 CNV 通常会导致严重且高度渗透的患者表型，但导致重复的 CNV 往往在受影响的个体中表现出广泛变化且渗透性较低的表型表达性。位于染色体 15q13.3 上的 CNV 影响 α-7 烟碱乙酰胆碱受体亚基 (CHRNA7) 基因，导致多种外显率高度可变的神经精神疾病。然而，这种差异外显率的基础仍然未知。在这里，我们从具有 15q13.3 重复的一级亲属中生成了诱导多能干细胞 (iPSC) 模型，并分析了它们的细胞表型，以揭示不同表型表达能力的基础。研究的一级亲属包括一名患有自闭症和情绪失调的男孩（受影响的先证者-AP）和他临床上未受影响的母亲（UM），并与缺乏这种重复的无关对照模型进行比较。在 iPSC 衍生的皮质兴奋性和抑制性神经元中对神经精神损伤的潜在因素进行了建模。 AP 衍生模型独特地表现出细胞生理学和神经发育的破坏，而在 UM 或不相关的对照中未观察到。这些包括神经祖细胞增殖增强，但神经元分化、成熟和迁移受损，以及内质网（ER）应激增加。不同的药物可以选择性地挽救神经元迁移缺陷和内质网应激升高。 AP 中的神经元基因表达也失调，包括与行为、心理障碍、神经突发生、神经元迁移、Wnt、轴突引导和 GABA 受体信号传导相关的基因表达减少。相反，UM 模型在许多相同途径中表现出基因表达上调，这表明分子补偿可能导致该模型中神经发育表型的缺乏。然而，AP 和 UM 衍生的神经元都表现出神经元功能的共同改变，包括动作电位放电增加和胆碱能活性升高，这与同聚 CHRNA7 通道活性增加一致。这些数据定义了与诊断相关的细胞表型和与 CHRNA7 重复相关的共享功能异常，这些异常可能导致 15q13.3 重复个体的表型外显率变化。药物能够挽救一些与诊断相关的神经发育异常，这为这种重复携带者和其他导致相关疾病的 CNV 的携带者提供了干预途径。