A Multiplex Human Pluripotent Stem Cell Platform Defines Molecular and Functional Subclasses of Autism-Related Genes.
Cell Stem Cell
; 27(1): 35-49.e6, 2020 07 02.
Article
em En
| MEDLINE
| ID: mdl-32619517
ABSTRACT
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/ßcatenin 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transtorno Autístico
/
Células-Tronco Pluripotentes
/
Transtornos do Neurodesenvolvimento
Limite:
Humans
Idioma:
En
Revista:
Cell Stem Cell
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos