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Peer-reviewedCC BY-NC-ND 4.0Communications Biology

KCTD3 deficiency disrupts axon initial segment organization and neurite outgrowth in a neurodevelopmental disorder mouse model

  • Yeonsoo Oh1
  • Youngha Lee2
  • Hoyong Jin1
  • Marcello Scala3,4
  • Valeria Capra5
  • Annalaura Torella6,7
  • Vincenzo Nigro6,7
  • Bertrand Isidor8
  • Frédéric Tran Mau-Them9,10
  • René G. Feichtinger11
  • Johannes A. Mayr11
  • Saskia B. Wortmann11
6 more authors
  • Hyeyoon Kim12,13
  • Dohyun Han12,14,15
  • Jin Sook Lee16
  • Jong-Hee Chae16,17
  • Murim Choi2
  • Yongcheol Cho1
17 affiliations
  1. 1Department of Brain Sciences, DGIST, Daegu, Republic of Korea
  2. 2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
  3. 3Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
  4. 4U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  5. 5Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  6. 6Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
  7. 7Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
  8. 8Service de génétique, CHU Nantes, Nantes, France
  9. 9UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France
  10. 10CHU Dijon Bourgogne, Service de Génomique Médicale, Laboratoire de Biologie Médicale, Dijon, France
  11. 11University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria
  12. 12Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
  13. 13Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
  14. 14Department of Transdisciplinary Medicine, Seoul National University Hospital, Seoul, Republic of Korea
  15. 15Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
  16. 16Department of Genomic Medicine, Seoul national University Hospital, Seoul, Republic of Korea
  17. 17Department of Pediatrics, Seoul national University College of Medicine, Seoul, Republic of Korea
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Abstract

Pathogenic variants in human KCTD3 are associated with severe neurodevelopmental disorders characterized by early-onset seizures, developmental delay, hypotonia, and cerebellar hypoplasia, but the underlying mechanisms remain unclear. Here we show that KCTD3 regulates neuronal structural organization through DAAM1, a protein involved in actin cytoskeleton assembly. In Kctd3-deficient neurons, DAAM1 protein levels are reduced, the axon initial segment is abnormally organized, and neurite growth and growth cone morphology are impaired. These defects are rescued by DAAM1 overexpression. Systemic Kctd3 depletion also disrupts axon initial segment organization and motor axon innervation at neuromuscular junctions, leading to motor dysfunction and growth impairment in mice. These findings identify a KCTD3-DAAM1 pathway required for neuronal structural development and provide a framework for understanding how KCTD3 deficiency contributes to neurodevelopmental disorders.

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Cite

BibTeXRIS
BibTeX
@article{oh2026kctd3,
  title = {{KCTD3 deficiency disrupts axon initial segment organization and neurite outgrowth in a neurodevelopmental disorder mouse model}},
  author = {Yeonsoo Oh and Youngha Lee and Hoyong Jin and Marcello Scala and Valeria Capra and Annalaura Torella and Vincenzo Nigro and Bertrand Isidor and Frédéric Tran Mau-Them and René G. Feichtinger and Johannes A. Mayr and Saskia B. Wortmann and Hyeyoon Kim and Dohyun Han and Jin Sook Lee and Jong-Hee Chae and Murim Choi and Yongcheol Cho},
  journal = {Communications Biology},
  year = {2026},
  month = jul,
  doi = {10.1038/s42003-026-10584-3},
  url = {https://doi.org/10.1038/s42003-026-10584-3},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - KCTD3 deficiency disrupts axon initial segment organization and neurite outgrowth in a neurodevelopmental disorder mouse model
AU  - Yeonsoo Oh
AU  - Youngha Lee
AU  - Hoyong Jin
AU  - Marcello Scala
AU  - Valeria Capra
AU  - Annalaura Torella
AU  - Vincenzo Nigro
AU  - Bertrand Isidor
AU  - Frédéric Tran Mau-Them
AU  - René G. Feichtinger
AU  - Johannes A. Mayr
AU  - Saskia B. Wortmann
AU  - Hyeyoon Kim
AU  - Dohyun Han
AU  - Jin Sook Lee
AU  - Jong-Hee Chae
AU  - Murim Choi
AU  - Yongcheol Cho
PY  - 2026
DA  - 2026/07/07
JO  - Communications Biology
DO  - 10.1038/s42003-026-10584-3
UR  - https://doi.org/10.1038/s42003-026-10584-3
AB  - Pathogenic variants in human KCTD3 are associated with severe neurodevelopmental disorders characterized by early-onset seizures, developmental delay, hypotonia, and cerebellar hypoplasia, but the underlying mechanisms remain unclear. Here we show that KCTD3 regulates neuronal structural organization through DAAM1, a protein involved in actin cytoskeleton assembly. In Kctd3-deficient neurons, DAAM1 protein levels are reduced, the axon initial segment is abnormally organized, and neurite growth and growth cone morphology are impaired. These defects are rescued by DAAM1 overexpression. Systemic Kctd3 depletion also disrupts axon initial segment organization and motor axon innervation at neuromuscular junctions, leading to motor dysfunction and growth impairment in mice. These findings identify a KCTD3-DAAM1 pathway required for neuronal structural development and provide a framework for understanding how KCTD3 deficiency contributes to neurodevelopmental disorders.
SN  - 2399-3642
ER  -