Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes.
Adolescent
Animals
Autistic Disorder
/ genetics
Behavior, Animal
Brain
/ pathology
Cell Differentiation
Cell Line
Cell Proliferation
Female
Gene Editing
Gene Knockdown Techniques
Genetic Predisposition to Disease
/ genetics
Heterozygote
Humans
Intellectual Disability
Male
Malformations of Cortical Development
/ genetics
Mice
Mice, Inbred C57BL
Middle Aged
Mutation
Neurodevelopmental Disorders
/ genetics
Neurogenesis
Neurons
/ metabolism
Phenotype
Transposases
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 02 2020
26 02 2020
Historique:
received:
05
07
2019
accepted:
28
01
2020
entrez:
28
2
2020
pubmed:
28
2
2020
medline:
24
4
2020
Statut:
epublish
Résumé
Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.
Identifiants
pubmed: 32103003
doi: 10.1038/s41467-020-14697-z
pii: 10.1038/s41467-020-14697-z
pmc: PMC7044294
doi:
Substances chimiques
POGZ protein, human
0
Transposases
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
859Références
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