RRC ID 58490
Author Matsumura K, Seiriki K, Okada S, Nagase M, Ayabe S, Yamada I, Furuse T, Shibuya H, Yasuda Y, Yamamori H, Fujimoto M, Nagayasu K, Yamamoto K, Kitagawa K, Miura H, Gotoda-Nishimura N, Igarashi H, Hayashida M, Baba M, Kondo M, Hasebe S, Ueshima K, Kasai A, Ago Y, Hayata-Takano A, Shintani N, Iguchi T, Sato M, Yamaguchi S, Tamura M, Wakana S, Yoshiki A, Watabe AM, Okano H, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T.
Title Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes.
Journal Nat Commun
Abstract 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.
Volume 11(1)
Pages 859
Published 2020-2-26
DOI 10.1038/s41467-020-14697-z
PII 10.1038/s41467-020-14697-z
PMID 32103003
PMC PMC7044294
MeSH 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*
IF 12.121
DNA material T7-NLS hCas9-pA (RDB13130)