️ Episode 126: Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models

In this episode of PaperCast Base by Base, we explore a study that investigates the molecular and developmental mechanisms underlying Smith-Magenis syndrome (SMS) using human induced pluripotent stem cell (hiPSC)-derived cortical models. The research focuses on how the deletion at chromosome 17p11.2 disrupts cortical development and contributes to neurological deficits.

Study Highlights:
The authors developed both 2D cortical neurons and 3D cortical organoids from SMS hiPSCs to model human corticogenesis. Hi-C analyses revealed widespread chromatin miswiring, including fusion and reorganization of topological domains. Single-nucleus RNA sequencing uncovered transcriptional signatures linked to neuropsychiatric disorders and dysregulation of genes involved in metabolism, the cell cycle, and neuronal signaling. SMS organoids exhibited reduced growth, ventriculomegaly-like features, impaired progenitor proliferation, and accelerated neuronal maturation. SMS cortical neurons also displayed increased dendritic growth followed by hyperexcitability due to reduced potassium conductance.

Conclusion:
This work demonstrates that deletion at 17p11.2 disrupts multiple stages of human cortical development, highlighting how chromatin architecture changes translate into transcriptional and neurophysiological abnormalities relevant to SMS.

Reference:
Lee YJ, Chang YT, Cho Y, Kowalczyk M, Dragoiescu A, Pacis A, Kailasam S, Lefebvre F, Zhang Q, Gao X, Huang WH. Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models. Am J Hum Genet. 2025 Oct 2;112(1):1–25. https://doi.org/10.1016/j.ajhg.2025.07.020

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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