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Peer-reviewedCC BYInternational journal of biological sciences

KAT6A-Mutant iPSC-Derived Cortical Neurons Display Precocious Maturation, Dysregulated Electrophysiology, and Altered Morphology.

  • Naama Wiesel-Motiuk1
  • Ashwani Choudhary2
  • Yara Hussein2
  • Utkarsh Tripathi2
  • Wote Amelo Rike2
  • Aviram Shemen2
  • Ritu Nayak2
  • Souvik Chakraborty2
  • Omveer Sharma2
  • Tatiana Rabinski3,4,5
  • Michal Stark1
  • Karin Weiss6,7
3 more authors
  • Gad D Vatine3,4,5
  • Shani Stern2
  • Yehuda G Assaraf1
7 affiliations
  1. 1The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
  2. 2Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel.
  3. 3The Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel.
  4. 4The Regenerative Medicine and Stem Cell (RMSC) Research Center. Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel.
  5. 5The Zelman Center of Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel.
  6. 6Genetic Institute, Rambam Health Care Campus, Haifa 3109601, Israel.
  7. 7Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3109601, Israel.
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Abstract

KAT6A syndrome is a complex neurodevelopmental disorder caused by heterozygous pathogenic KAT6A variants inflicting variable degrees of developmental delay and intellectual disability via a mechanism that remains largely uncharacterized. To further our understanding, we differentiated KAT6A syndrome patient-derived induced pluripotent stem cells into neural progenitor cells and cortical neurons. KAT6A syndrome patient-derived cells exhibit an altered transcriptome, with many of the dysregulated genes associated with autism spectrum disorder. At an early stage of differentiation, KAT6A-mutant cortical neurons show many elevated neurodevelopment-specific genes, including key transcription factors. Detailed electrophysiological measurements uncover that KAT6A-mutant cortical neurons display a hyperexcitability phenotype at an early stage of differentiation, followed by hypoexcitability at a later stage, compared with control neurons. These electrophysiological alterations were accompanied by decreased sodium and potassium currents. Remarkably, early KAT6A-mutant neurons exhibit a markedly lower percentage of GABA-positive neurons and increased spontaneous calcium activity as compared with control neurons. Moreover, multiple morphometric alterations in early-stage KAT6A-mutant cortical neurons indicate premature maturation, including increased neurite outgrowth, arbor complexity and soma size. Consistently, KAT6A knockout SH-SY5Y cells exhibit impaired differentiation capability and dysregulated gene expression. These novel findings establish the deleterious impact of pathogenic KAT6A variants on cortical neuron differentiation and electrophysiological function.

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Cite

BibTeXRIS
BibTeX
@article{wieselmotiuk2026kat6amutant,
  title = {{KAT6A-Mutant iPSC-Derived Cortical Neurons Display Precocious Maturation, Dysregulated Electrophysiology, and Altered Morphology.}},
  author = {Naama Wiesel-Motiuk and Ashwani Choudhary and Yara Hussein and Utkarsh Tripathi and Wote Amelo Rike and Aviram Shemen and Ritu Nayak and Souvik Chakraborty and Omveer Sharma and Tatiana Rabinski and Michal Stark and Karin Weiss and Gad D Vatine and Shani Stern and Yehuda G Assaraf},
  journal = {International journal of biological sciences},
  year = {2026},
  month = sep,
  doi = {10.7150/ijbs.134210},
  url = {https://europepmc.org/article/MED/42909968},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - KAT6A-Mutant iPSC-Derived Cortical Neurons Display Precocious Maturation, Dysregulated Electrophysiology, and Altered Morphology.
AU  - Naama Wiesel-Motiuk
AU  - Ashwani Choudhary
AU  - Yara Hussein
AU  - Utkarsh Tripathi
AU  - Wote Amelo Rike
AU  - Aviram Shemen
AU  - Ritu Nayak
AU  - Souvik Chakraborty
AU  - Omveer Sharma
AU  - Tatiana Rabinski
AU  - Michal Stark
AU  - Karin Weiss
AU  - Gad D Vatine
AU  - Shani Stern
AU  - Yehuda G Assaraf
PY  - 2026
DA  - 2026/09/24
JO  - International journal of biological sciences
DO  - 10.7150/ijbs.134210
UR  - https://europepmc.org/article/MED/42909968
AB  - KAT6A syndrome is a complex neurodevelopmental disorder caused by heterozygous pathogenic KAT6A variants inflicting variable degrees of developmental delay and intellectual disability via a mechanism that remains largely uncharacterized. To further our understanding, we differentiated KAT6A syndrome patient-derived induced pluripotent stem cells into neural progenitor cells and cortical neurons. KAT6A syndrome patient-derived cells exhibit an altered transcriptome, with many of the dysregulated genes associated with autism spectrum disorder. At an early stage of differentiation, KAT6A-mutant cortical neurons show many elevated neurodevelopment-specific genes, including key transcription factors. Detailed electrophysiological measurements uncover that KAT6A-mutant cortical neurons display a hyperexcitability phenotype at an early stage of differentiation, followed by hypoexcitability at a later stage, compared with control neurons. These electrophysiological alterations were accompanied by decreased sodium and potassium currents. Remarkably, early KAT6A-mutant neurons exhibit a markedly lower percentage of GABA-positive neurons and increased spontaneous calcium activity as compared with control neurons. Moreover, multiple morphometric alterations in early-stage KAT6A-mutant cortical neurons indicate premature maturation, including increased neurite outgrowth, arbor complexity and soma size. Consistently, KAT6A knockout SH-SY5Y cells exhibit impaired differentiation capability and dysregulated gene expression. These novel findings establish the deleterious impact of pathogenic KAT6A variants on cortical neuron differentiation and electrophysiological function.
SN  - 1449-2288
ER  -