A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• A pathogenic de novo p.R342W mutation in CTBP1 was previously identified in patients with neurodevelopmental disabilities.
• This study investigates seven additional individuals with the same recurrent mutation.

Purpose of the Study:

• To characterize the clinical phenotypes associated with the CTBP1 p.R342W mutation.
• To elucidate the molecular mechanisms underlying the observed phenotypes.

Main Methods:

• Clinical evaluation of affected individuals.
• Proteomic analysis to assess protein interactions.
• Genome-wide transcriptome analysis.
• Apoptosis assays in patient-derived fibroblasts under glucose deprivation.

Main Results:

• Consistent phenotypes including intellectual disability, ataxia, hypotonia, and tooth enamel defects were observed.
• The R342W mutation reduced interactions between CTBP1 and chromatin-modifying factors.
• Gene expression profiles were altered, affecting multiple cellular processes.
• Patient fibroblasts showed increased sensitivity to apoptosis, linked to NOXA gene activation during glucose deprivation.

Conclusions:

• The CTBP1 R342W mutation leads to neurodevelopmental phenotypes through disrupted protein interactions and altered gene expression.
• Deregulation of apoptosis, potentially via NOXA, contributes to the pathogenesis.
• Context-dependent relief of transcriptional repression by the mutant CTBP1 may play a role in disease development.