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Isogenic iPSC-derived CTBP1 mutant neuronal cells exhibit neurodevelopmental defects
Suhjin Lee1, Selvamani Vijayalingam2, Elliott Klotz3
1Department of Health Management and Policy, College of Public Health and Social Justice, Saint Louis University, St. Louis, MO, United States.
Frontiers in Neuroscience
|December 29, 2025
Summary
Hypotonia, ataxia, developmental delay, and tooth enamel defects syndrome (HADDTS) is caused by CTBP1 mutations. Our study reveals how CTBP1 mutations disrupt neurodevelopment by altering gene expression and cell function.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Hypotonia, ataxia, developmental delay, and tooth enamel defects syndrome (HADDTS) is a rare genetic disorder.
- It is associated with mutations in the CTBP1 gene, which encodes a transcriptional corepressor.
Purpose of the Study:
- To investigate the functional consequences of the predominant CTBP1 p.R342W mutation.
- To understand the mutation's role in neurodevelopmental defects.
Main Methods:
- Generated isogenic induced pluripotent stem cell (iPSC) lines with CTBP1 mutations (heterozygous and homozygous) using CRISPR/Cas9.
- Performed genome-wide RNA sequencing on iPSC-derived early neurons.
- Assessed neural stem cell (NSC) adhesion, migration, and calcium signaling, and neuronal neurite outgrowth.
Main Results:
- CTBP1 mutations led to downregulation of key transcription factors, with homozygous mutations having a more significant effect.
- Mutant NSCs showed impaired adhesion and migration, and dysregulated calcium signaling.
- Mutant neurons exhibited premature neurite outgrowth.
Conclusions:
- The CTBP1 p.R342W mutation disrupts neurodevelopmental processes.
- Transcriptomic and cellular data provide insights into the molecular mechanisms underlying HADDTS.
