CTBP1 In Brain Development: A Novel Variant c.107G>C,p.(R36P) Leads to a Distinct Neurodevelopmental Disorder.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• C-terminal-binding protein 1 (CTBP1) is crucial for gene regulation and cellular processes.
• CTBP1 variants are linked to HADDTS (Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome), but its role in neurodevelopment is not fully understood.

Purpose of the Study:

• To investigate the pathophysiological mechanism of a novel CTBP1 variant (p.R36P) found in a patient with neurodevelopmental issues.
• To compare the effects of the novel p.R36P variant with a known pathogenic CTBP1 variant (p.R342W) associated with HADDTS.

Main Methods:

• Whole exome sequencing identified a de novo CTBP1 variant (p.R36P).
• In vitro and in vivo studies using primary hippocampal neurons and mouse models.
• Electrophysiological analyses were performed to assess neuronal function.

Main Results:

• Both p.R36P and p.R342W CTBP1 variants impaired dendritic development and neuronal migration.
• These variants reduced excitatory synaptic transmission, impacting neuronal communication.
• The p.R36P variant uniquely decreased the excitability of specific pyramidal neurons.

Conclusions:

• CTBP1 is essential for normal brain development.
• The novel CTBP1 p.R36P variant may lead to a distinct neurodevelopmental disorder.
• Understanding CTBP1 variant effects is critical for diagnosing and potentially treating neurodevelopmental disorders.