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 Kondo; Shigeru 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

doi:10.1038/s41467-020-14697-z

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

Department of Physiology

Research output: Contribution to journal › Article › peer-review

44 Citations (Scopus)

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 language	English
Article number	859
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14697-z
Publication status	Published - 2020 Dec 1

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(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), Article 859. https://doi.org/10.1038/s41467-020-14697-z

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 2020, 'Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes', Nature communications, vol. 11, no. 1, 859. https://doi.org/10.1038/s41467-020-14697-z

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title = "Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes",

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.",

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

note = "Funding Information: We thank Dr. Masataka Kikuchi for helpful discussion. We acknowledge the NGS core facility of the Genome Information Research Center at the Research Institute for Microbial Diseases of Osaka University for the support in RNA sequencing and data analysis. This work was supported in part by JSPS KAKENHI, grant numbers JP15H04645 (T.N.), JP18H02574 (T.N.), JP17K19488 (H.H.), JP17H03989 (H.H.), JP16K07004 (A.M.W.) and JP17H05960 (A.M.W.); the JSPS Research Fellowships for Young Scientists, grant number JP17J00152 (K.M.); JST CREST, grant number JPMJCR1751 (A.M.W.); MEXT KAKENHI, grant numbers JP18H05416 (H.H.), JP19H05217 (A.K.), JP19H04909 (T.N.) and JP19H05218 (T.N.); AMED, grant numbers JP19gm1310003 (T.N.), JP18dm0107122 (H.H.), JP18dm0207061 (H.H.), and JP18am0101084; Nagai Memorial Research Scholarship, Pharmaceutical Society of Japan (K.M.); and grants from the Takeda Science Foundation (T.N.), the Japan Foundation for Pediatric Research (T.N.), the Asahi Glass Foundation (T.N.), and the Pharmacological Research Foundation, Tokyo (T.N.). This study was also supported in part by Center for Medical Research and Education, Graduate School of Medicine, Osaka University. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-14697-z",

language = "English",

volume = "11",

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T1 - Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes

AU - Matsumura, Kensuke

AU - Seiriki, Kaoru

AU - Okada, Shota

AU - Nagase, Masashi

AU - Ayabe, Shinya

AU - Yamada, Ikuko

AU - Furuse, Tamio

AU - Shibuya, Hirotoshi

AU - Yasuda, Yuka

AU - Yamamori, Hidenaga

AU - Fujimoto, Michiko

AU - Nagayasu, Kazuki

AU - Yamamoto, Kana

AU - Kitagawa, Kohei

AU - Miura, Hiroki

AU - Gotoda-Nishimura, Nanaka

AU - Igarashi, Hisato

AU - Hayashida, Misuzu

AU - Baba, Masayuki

AU - Kondo, Momoka

AU - Hasebe, Shigeru

AU - Ueshima, Kosei

AU - Kasai, Atsushi

AU - Ago, Yukio

AU - Hayata-Takano, Atsuko

AU - Shintani, Norihito

AU - Iguchi, Tokuichi

AU - Sato, Makoto

AU - Yamaguchi, Shun

AU - Tamura, Masaru

AU - Wakana, Shigeharu

AU - Yoshiki, Atsushi

AU - Watabe, Ayako M.

AU - Okano, Hideyuki

AU - Takuma, Kazuhiro

AU - Hashimoto, Ryota

AU - Hashimoto, Hitoshi

AU - Nakazawa, Takanobu

N1 - Funding Information: We thank Dr. Masataka Kikuchi for helpful discussion. We acknowledge the NGS core facility of the Genome Information Research Center at the Research Institute for Microbial Diseases of Osaka University for the support in RNA sequencing and data analysis. This work was supported in part by JSPS KAKENHI, grant numbers JP15H04645 (T.N.), JP18H02574 (T.N.), JP17K19488 (H.H.), JP17H03989 (H.H.), JP16K07004 (A.M.W.) and JP17H05960 (A.M.W.); the JSPS Research Fellowships for Young Scientists, grant number JP17J00152 (K.M.); JST CREST, grant number JPMJCR1751 (A.M.W.); MEXT KAKENHI, grant numbers JP18H05416 (H.H.), JP19H05217 (A.K.), JP19H04909 (T.N.) and JP19H05218 (T.N.); AMED, grant numbers JP19gm1310003 (T.N.), JP18dm0107122 (H.H.), JP18dm0207061 (H.H.), and JP18am0101084; Nagai Memorial Research Scholarship, Pharmaceutical Society of Japan (K.M.); and grants from the Takeda Science Foundation (T.N.), the Japan Foundation for Pediatric Research (T.N.), the Asahi Glass Foundation (T.N.), and the Pharmacological Research Foundation, Tokyo (T.N.). This study was also supported in part by Center for Medical Research and Education, Graduate School of Medicine, Osaka University. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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

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