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The patient-specific mouse model with Foxg1 frameshift mutation provides insights into the pathophysiology of FOXG1 syndrome

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Listed:
  • Shin Jeon

    (The State University of New York (SUNY)
    The State University of New York (SUNY)
    University of Pennsylvania)

  • Jaein Park

    (The State University of New York (SUNY)
    The State University of New York (SUNY))

  • Ji Hwan Moon

    (The State University of New York (SUNY)
    The State University of New York (SUNY)
    Samsung Medical Center)

  • Dongjun Shin

    (The State University of New York (SUNY)
    The State University of New York (SUNY))

  • Liwen Li

    (The State University of New York (SUNY)
    The State University of New York (SUNY))

  • Holly O’Shea

    (The State University of New York (SUNY)
    The State University of New York (SUNY))

  • Seon-Ung Hwang

    (The State University of New York (SUNY)
    The State University of New York (SUNY))

  • Hyo-Jong Lee

    (Sungkyunkwan University)

  • Elise Brimble

    (Port Washington
    San Francisco)

  • Jae W. Lee

    (The State University of New York (SUNY)
    The State University of New York (SUNY))

  • Stewart D. Clark

    (The State University of New York (SUNY))

  • Soo-Kyung Lee

    (The State University of New York (SUNY)
    The State University of New York (SUNY))

Abstract

Single allelic mutations in the FOXG1 gene lead to FOXG1 syndrome (FS). To understand the pathophysiology of FS, which vary depending on FOXG1 mutation types, patient-specific animal models are critical. Here, we report a patient-specific Q84Pfs heterozygous (Q84Pfs-Het) mouse model, which recapitulates various FS phenotypes across cellular, brain structural, and behavioral levels. Q84Pfs-Het cortex shows dysregulations of genes controlling cell proliferation, neuronal projection and migration, synaptic assembly, and synaptic vesicle transport. The Q84Pfs allele produces the N-terminal fragment of FOXG1 (Q84Pfs protein) in Q84Pfs-Het mouse brains, which forms intracellular speckles, interacts with FOXG1 full-length protein, and triggers the sequestration of FOXG1 to distinct subcellular domains. Q84Pfs protein promotes the radial glial cell identity and suppresses neuronal migration in the cortex. Our study uncovers the role of the FOXG1 fragment from FS-causing FOXG1 variants and identifies the genes involved in FS-like cellular and behavioral phenotypes, providing insights into the pathophysiology of FS.

Suggested Citation

  • Shin Jeon & Jaein Park & Ji Hwan Moon & Dongjun Shin & Liwen Li & Holly O’Shea & Seon-Ung Hwang & Hyo-Jong Lee & Elise Brimble & Jae W. Lee & Stewart D. Clark & Soo-Kyung Lee, 2025. "The patient-specific mouse model with Foxg1 frameshift mutation provides insights into the pathophysiology of FOXG1 syndrome," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59838-4
    DOI: 10.1038/s41467-025-59838-4
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    References listed on IDEAS

    as
    1. Pei-Shan Hou & Goichi Miyoshi & Carina Hanashima, 2019. "Sensory cortex wiring requires preselection of short- and long-range projection neurons through an Egr-Foxg1-COUP-TFI network," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    2. Goichi Miyoshi & Yoshifumi Ueta & Akiyo Natsubori & Kou Hiraga & Hironobu Osaki & Yuki Yagasaki & Yusuke Kishi & Yuchio Yanagawa & Gord Fishell & Robert P. Machold & Mariko Miyata, 2021. "FoxG1 regulates the formation of cortical GABAergic circuit during an early postnatal critical period resulting in autism spectrum disorder-like phenotypes," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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