Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes

Kensuke Matsumura, Kaoru Seiriki, Shota Okada, Masashi Nagase, Shinya Ayabe, Ikuko Yamada, Tamio Furuse, Hirotoshi Shibuya, Yuka Yasuda, Hidenaga Yamamori, Michiko Fujimoto, Kazuki Nagayasu, Kana Yamamoto, Kohei Kitagawa, Hiroki Miura, Nanaka Gotoda-Nishimura, Hisato Igarashi, Misuzu Hayashida, Masayuki Baba, Momoka KondoShigeru Hasebe, Kosei Ueshima, Atsushi Kasai, Yukio Ago, Atsuko Hayata-Takano, Norihito Shintani, Tokuichi Iguchi, Makoto Sato, Shun Yamaguchi, Masaru Tamura, Shigeharu Wakana, Atsushi Yoshiki, Ayako M. Watabe, Hideyuki Okano, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number859
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    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., ... Nakazawa, T. (2020). Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. Nature communications, 11(1), [859]. https://doi.org/10.1038/s41467-020-14697-z