論文

査読有り 筆頭著者 本文へのリンクあり 国際誌
2020年7月

A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders.

Annals of clinical and translational neurology
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回数 : 83
  • Toshimitsu Suzuki
  • Toshifumi Suzuki
  • Matthieu Raveau
  • Noriko Miyake
  • Genki Sudo
  • Yoshinori Tsurusaki
  • Takaki Watanabe
  • Yuki Sugaya
  • Tetsuya Tatsukawa
  • Emi Mazaki
  • Atsushi Shimohata
  • Itaru Kushima
  • Branko Aleksic
  • Tomoko Shiino
  • Tomoko Toyota
  • Yoshimi Iwayama
  • Kentaro Nakaoka
  • Iori Ohmori
  • Aya Sasaki
  • Ken Watanabe
  • Shinichi Hirose
  • Sunao Kaneko
  • Yushi Inoue
  • Takeo Yoshikawa
  • Norio Ozaki
  • Masanobu Kano
  • Takeyoshi Shimoji
  • Naomichi Matsumoto
  • Kazuhiro Yamakawa
  • 全て表示

7
7
開始ページ
1117
終了ページ
1131
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/acn3.51093
出版者・発行元
Wiley

OBJECTIVE: Neurodevelopmental disorders (NDDs) often associate with epilepsy or craniofacial malformations. Recent large-scale DNA analyses identified hundreds of candidate genes for NDDs, but a large portion of the cases still remain unexplained. We aimed to identify novel candidate genes for NDDs. METHODS: We performed exome sequencing of 95 patients with NDDs including 51 with trigonocephaly and subsequent targeted sequencing of additional 463 NDD patients, functional analyses of variant in vitro, and evaluations of autism spectrum disorder (ASD)-like phenotypes and seizure-related phenotypes in vivo. RESULTS: We identified de novo truncation variants in nine novel genes; CYP1A1, C14orf119, FLI1, CYB5R4, SEL1L2, RAB11FIP2, ZMYND8, ZNF143, and MSX2. MSX2 variants have been described in patients with cranial malformations, and our present patient with the MSX2 de novo truncation variant showed cranial meningocele and partial epilepsy. MSX2 protein is known to be ubiquitinated by an E3 ubiquitin ligase PJA1, and interestingly we found a PJA1 hemizygous p.Arg376Cys variant recurrently in seven Japanese NDD patients; five with trigonocephaly and one with partial epilepsy, and the variant was absent in 886 Japanese control individuals. Pja1 knock-in mice carrying p.Arg365Cys, which is equivalent to p.Arg376Cys in human, showed a significant decrease in PJA1 protein amount, suggesting a loss-of-function effect of the variant. Pja1 knockout mice displayed moderate deficits in isolation-induced ultrasonic vocalizations and increased seizure susceptibility to pentylenetetrazole. INTERPRETATION: These findings propose novel candidate genes including PJA1 and MSX2 for NDDs associated with craniofacial abnormalities and/or epilepsy.

リンク情報
DOI
https://doi.org/10.1002/acn3.51093
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32530565
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359110
URL
https://onlinelibrary.wiley.com/doi/pdf/10.1002/acn3.51093
URL
https://onlinelibrary.wiley.com/doi/full-xml/10.1002/acn3.51093
URL
https://onlinelibrary.wiley.com/doi/am-pdf/10.1002%2Facn3.51093
ID情報
  • DOI : 10.1002/acn3.51093
  • ISSN : 2328-9503
  • eISSN : 2328-9503
  • PubMed ID : 32530565
  • PubMed Central 記事ID : PMC7359110

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