Autism-specific PTEN p.I135L mutation and an autism genetic background combine to dysregulate cortical neurogenesis

Abstract

Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). The contribution of genetic backgrounds, in additional to ASD risk genes, on cortical neurogenesis remain understudied. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN p.I135L mutation found in an ASD patient with macrocephaly activates PI3K/AKT and dysregulates cortical neurogenesis in an ASD genetic background-dependent fashion. Transcriptome analysis at both bulk and single cell level revealed PTEN p.I135L mutation and ASD genetic background affected genes involved in neurogenesis, neural development and synapse signaling. We also found that this PTEN p.I135L mutation 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 a PTEN p.I135L mutation and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.