Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA.
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
Am J Hum Genet. 2023 May 4;110(5):826-845. doi: 10.1016/j.ajhg.2023.03.015. Epub 2023 Apr 24.
Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). The contribution of genetic backgrounds, in addition to ASD risk genes, on cortical neurogenesis remains understudied. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN c.403A>C (p.Ile135Leu) variant found in an ASD-affected individual with macrocephaly dysregulates cortical neurogenesis in an ASD-genetic-background-dependent fashion. Transcriptome analysis at both bulk and single-cell level revealed that the PTEN c.403A>C variant and ASD genetic background affected genes involved in neurogenesis, neural development, and synapse signaling. We also found that this PTEN p.Ile135Leu variant led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. These findings provide experimental evidence that both the PTEN p.Ile135Leu variant and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.
皮质神经发生的改变与神经发育障碍有关，包括自闭症谱系障碍（ASD）。除了 ASD 风险基因外，遗传背景对皮质神经发生的影响仍研究不足。在这里，我们使用同基因诱导多能干细胞（iPSC）衍生的神经祖细胞（NPC）和皮质类器官模型，报告了在一个患有大头畸形的 ASD 患者中发现的杂合性 PTEN c.403A>C（p.Ile135Leu）变体以一种依赖于 ASD 遗传背景的方式调节皮质神经发生。在 bulk 和单细胞水平的转录组分析表明，PTEN c.403A>C 变体和 ASD 遗传背景影响涉及神经发生、神经发育和突触信号的基因。我们还发现，这种 PTEN p.Ile135Leu 变体导致 NPC 亚型以及神经元亚型（包括深层和浅层神经元）的过度产生，而在引入对照遗传背景时则不会。这些发现提供了实验证据，表明 PTEN p.Ile135Leu 变体和 ASD 遗传背景都导致与大头畸形相关的符合 ASD 的细胞特征。
