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ORIGINAL RESEARCH article

Front. Neurosci.

Sec. Neurodevelopment

Isogenic iPSC-Derived CTBP1 Mutant Neuronal Cells Exhibit Neurodevelopmental Defects

Provisionally accepted
Suhjin LeeSuhjin Lee1Selvamani VijayalingamSelvamani Vijayalingam2Elliott KlotzElliott Klotz3Cass DedertCass Dedert4Fenglian XuFenglian Xu4Govindaswamy ChinnaduraiGovindaswamy Chinnadurai5Uthayashanker R EzekielUthayashanker R Ezekiel6*
  • 1Saint Louis University College for Public Health and Social Justice, St. Louis, United States
  • 2Genome Engineering and Stem Cell Center (GESC@MGI), Department of Genetics, Washington University School of Medicine in St. Louis, Saint Louis, United States
  • 3Washington University in St Louis McDonnell Genome Institute, St. Louis, United States
  • 4Saint Louis University College of Arts and Sciences, St. Louis, United States
  • 5Saint Louis University Department of Molecular Microbiology and Immunology, St. Louis, United States
  • 6Clinical Laboratory Science, Saint Louis University, St. Louis, MO, United States

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Hypotonia, ataxia, developmental delay, and tooth enamel defects syndrome (HADDTS) is a recently identified disorder linked to a heterozygous mutation in the C-terminal Binding Protein 1 (CTBP1) transcriptional corepressor. The predominant mutation (p.R342W) is located within the major protein binding cleft (PXDLS), crucial for CtBP1's interaction with transcriptional regulatory proteins. To investigate the mutation's functional consequences, we generated isogenic induced pluripotent cell lines (iPSCs) carrying the CTBP1 mutation in heterozygous and homozygous conditions using the CRISPR/Cas9 editing method. The transcriptional profile of iPSC-derived early neurons from isogenic wild-type and CTBP1 heterozygous and homozygous mutants was determined by genome-wide RNA sequencing. The RNA-Seq data revealed downregulation of several key transcription factors, with homozygous mutations causing more pronounced downregulation compared to heterozygous mutations. Isogenic mutant neural stem cells (NSCs) exhibited reduced adhesion and migration, along with dysregulated calcium signaling, while mutant neurons showed premature neurite outgrowth. Together, our transcriptomic and biological results provide novel insights into the role and mechanism of CTBP1 p.R342W mutation in the defective neurodevelopmental processes.

Keywords: CtBP1, de novo mutation, HADDTS, transcriptional repression, isogenic cells

Received: 29 Aug 2025; Accepted: 17 Nov 2025.

Copyright: © 2025 Lee, Vijayalingam, Klotz, Dedert, Xu, Chinnadurai and Ezekiel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Uthayashanker R Ezekiel, uthayashanker.ezekiel@health.slu.edu

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material