A Multiplex Human Pluripotent Stem Cell Platform Defines Molecular and Functional Subclasses of Autism-Related Genes
| Autor: | Chelsea Rittenhouse, Scott J. Callahan, Sun Young Chung, Ting Zhou, Mark J. Tomishima, Sean D. Ryan, Lorenz Studer, Chao Zhang, Jason Tchieu, Nadja Zeltner, Doron Betel, Richard M. White, Kiran Ramnarine, Gustav Y. Cederquist, Shuibing Chen |
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| Rok vydání: | 2020 |
| Předmět: |
Pluripotent Stem Cells
Neurogenesis Induced Pluripotent Stem Cells Biology Article 03 medical and health sciences 0302 clinical medicine Neurodevelopmental disorder mental disorders Genetics medicine Humans Heritability of autism Autistic Disorder Induced pluripotent stem cell 030304 developmental biology 0303 health sciences Genetic heterogeneity Wnt signaling pathway Cell Differentiation Cell Biology medicine.disease Neurodevelopmental Disorders Mutation Molecular Medicine Autism Neuroscience Neural development 030217 neurology & neurosurgery |
| Zdroj: | Cell Stem Cell |
| ISSN: | 1934-5909 |
| Popis: | Autism is a clinically heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restricted interests, and repetitive behaviors. Despite significant advances in the genetics of autism, understanding how genetic changes perturb brain development and affect clinical symptoms remains elusive. Here, we present a multiplex human pluripotent stem cell (hPSC) platform, in which 30 isogenic disease lines are pooled in a single dish and differentiated into prefrontal cortex (PFC) lineages to efficiently test early-developmental hypotheses of autism. We define subgroups of autism mutations that perturb PFC neurogenesis and are correlated to abnormal WNT/βcatenin responses. Class 1 mutations (8 of 27) inhibit while class 2 mutations (5 of 27) enhance PFC neurogenesis. Remarkably, autism patient data reveal that individuals carrying subclass-specific mutations differ clinically in their corresponding language acquisition profiles. Our study provides a framework to disentangle genetic heterogeneity associated with autism and points toward converging molecular and developmental pathways of diverse autism-associated mutations. |
| Databáze: | OpenAIRE |
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