Human iPSC-Derived Neuronal Cells From CTBP1-Mutated Patients Reveal Altered Expression of Neurodevelopmental Gene...

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• A recurrent de novo mutation in CTBP1 is linked to neurodevelopmental disorders.
• The mutation (p.R342W) affects the cofactor recruitment domain of CtBP1.
• Understanding the pathogenic mechanism requires studying the mutant allele in relevant cellular models.

Purpose of the Study:

• To investigate the transcriptional activity of the CTBP1 p.R342W mutant allele.
• To create and analyze patient-derived induced pluripotent stem cells (iPSCs) and their neuronal derivatives.
• To elucidate the molecular and cellular consequences of the CTBP1 mutation.

Main Methods:

• Generation of iPSCs from patient and donor fibroblasts.
• Differentiation of iPSCs into early neurons.
• RNA-sequencing to compare transcriptional profiles.
• Morphological and electrophysiological assessments of neurons.
• Assessment of viral susceptibility.

Main Results:

• Patient-derived neurons showed downregulated gene networks crucial for neurodevelopment, synaptic adhesion, and antiviral responses.
• Neurons exhibited morphological and electrophysiological abnormalities.
• Patient-derived neurons displayed increased susceptibility to viral infection.

Conclusions:

• The CTBP1 p.R342W mutation disrupts neurodevelopmental gene networks.
• iPSC-derived neuron models effectively recapitulate patient phenotypes.
• These findings offer insights into the pathological mechanisms of CTBP1-associated neurodevelopmental disabilities.