USP15 mutation associated with autism spectrum disorder alters progenitor fate and neuronal maturation in human brain organoids.
Overview
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea
- Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea
- National Research Laboratory for Convergence Degradation Biology, Korea University, Seoul, Republic of Korea
- Department of Life Science, Ewha Womans University, Seoul, Republic of Korea
- School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea
- Department of Biochemistry & Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
- Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, British Columbia V5Z 1L3, Canada
- Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Republic of Korea
Abstract
De novo variants in the ubiquitin-proteasome pathway are linked to autism spectrum disorder (ASD), yet their functional impact on neurodevelopment remains poorly understood. We investigated USP15, a deubiquitinating enzyme with rare damaging variants identified in individuals with ASD, using isogenic human iPSC-derived brain organoids and single-cell transcriptomics. USP15 mutant organoids showed genotype-dependent, progenitor-centered alterations during corticogenesis. Heterozygous organoids modeling haploinsufficiency displayed a shift toward later pseudotime states together with altered maturation and synaptic organization of deep-layer neurons. In contrast, homozygous organoids showed broader phenotypes, including mitotic suppression, aberrant HOX gene expression, and stress-response activation. Regulon analysis showed reduced activity of progenitor-associated regulons, including SOX2, NR2F1, and NR2F2, in heterozygous organoids, whereas homozygous organoids exhibited broader changes in transcriptional regulatory networks. Furthermore, USP15 mutant-associated gene expression patterns were significantly enriched for established ASD risk genes. Comparison with the mouse brain perturbation atlas showed that the transcriptional signature of the USP15 mutant showed notable overlap with those of Fezf2 and Foxp1 mutants, key regulators of deep-layer projection neuron identity. These findings characterize genotype-dependent neurodevelopmental phenotypes associated with reduced USP15 dosage and provide a human neural framework for investigating ASD-relevant developmental mechanisms in the context of a rare ubiquitin-pathway variant.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- zenodo:17112344, at Zenodo; found in the text, “Differentially Expressed Genes Analysis of…”
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 2, 28 September 2026
- Authors: added Tae-Hwan Park (0009-0003-3047-7264); In Gyeong Koh (0009-0008-8228-1622); Seoyoung Sung (0009-0006-9917-9742); Hayoon Park (0009-0002-1956-4044); Jieun Kim (0000-0002-7429-3403); Sebin Lee (0009-0004-1557-4223); Yun Jin Lee (0009-0001-8363-0475); Hyunsoo Ko (0009-0005-9460-6015); Guiyoung Bong (0000-0001-8630-9399); Hee Jeong Yoo (0000-0003-0521-2718); Jaesang Kim (0000-0002-7659-4242); Joon-Yong An (0000-0001-8839-6297); Ji Yeoun Lee (0000-0003-0464-7605); removed Tae-Hwan Park; In Gyeong Koh; Seoyoung Sung; Hayoon Park; Jieun Kim; Sebin Lee; Yun Jin Lee; Hyunsoo Ko; Guiyoung Bong; Hee Jeong Yoo; Jaesang Kim; Joon-Yong An; Ji Yeoun Lee
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 5 keywords, 11 MeSH terms, 3 funders, 80 references.
Cite
This paper
Park, T.-H., Koh, I. G., Sung, S., Park, H., Kim, J., Lee, S., Lee, Y. J., Ko, H., Han, J. H., Bong, G., Yoo, H. J., Kim, J., An, J.-Y., & Lee, J. Y. (2026). USP15 mutation associated with autism spectrum disorder alters progenitor fate and neuronal maturation in human brain organoids. Molecules and cells, 49(9), 100387. https://
BibTeX
@article{park2026usp15,
author = {Park, Tae-Hwan and Koh, In Gyeong and Sung, Seoyoung and Park, Hayoon and Kim, Jieun and Lee, Sebin and Lee, Yun Jin and Ko, Hyunsoo and Han, Jae Hyun and Bong, Guiyoung and Yoo, Hee Jeong and Kim, Jaesang and An, Joon-Yong and Lee, Ji Yeoun},
title = {{USP15 mutation associated with autism spectrum disorder alters progenitor fate and neuronal maturation in human brain organoids}},
journal = {Molecules and cells},
year = {2026},
month = jul,
volume = {49},
number = {9},
pages = {100387},
publisher = {Korean Society for Molecular and Cellular Biology},
issn = {1016-8478},
doi = {10.1016/
url = {https://
pmid = {42526765},
pmcid = {PMC13499480}
}
RIS
TY - JOUR
AU - Park, Tae-Hwan
AU - Koh, In Gyeong
AU - Sung, Seoyoung
AU - Park, Hayoon
AU - Kim, Jieun
AU - Lee, Sebin
AU - Lee, Yun Jin
AU - Ko, Hyunsoo
AU - Han, Jae Hyun
AU - Bong, Guiyoung
AU - Yoo, Hee Jeong
AU - Kim, Jaesang
AU - An, Joon-Yong
AU - Lee, Ji Yeoun
TI - USP15 mutation associated with autism spectrum disorder alters progenitor fate and neuronal maturation in human brain organoids
T2 - Molecules and cells
J2 - Mol Cells
PY - 2026
DA - 2026/
VL - 49
IS - 9
SP - 100387
SN - 1016-8478
PB - Korean Society for Molecular and Cellular Biology
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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