Insights into CTBP1 dysfunction in HADDTS: Linking the metabolic and neurodevelopmental dysfunction

C-terminal binding protein 1 (CTBP1) is a ubiquitously expressed transcriptional co-repressor protein that controls gene expression dependently of metabolic state of the cell. The recurrent mutation in the CTBP1 gene (CTBP1R331W) is associated with Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome (HADDTS). Our study aims to elucidate how CTBP1R331W contributes to the neurodevelopmental defects observed in HADDTS. Recent studies have identified aberrant cellular metabolism in the muscle tissue of HADDTS patients, yet the molecular link between metabolic dysfunction and neurodevelopmental issues in HADDTS remains unclear. In our study, we have found that initial problem arises during pluripotency state of the cells. The CTBP1R331W variant leads to reduced pluripotency, diminished self-renewal capacity, lowered cellular proliferation rate, reduced cellular adhesion, and decreased glycolysis . Additionally, during differentiation into ectoderm derivatives, we observed downregulation of expression profiles of ectoderm lineage marker genes (i.e. NEST, MCM2, SOX2) and mature neuron markers (i.e. TUBB3, NEUN, CALB) while nonneuronal markers (i.e. OLIG2, GFAP) were found to be upregulated during neuronal induction. These findings suggest that the expression of the CTBP1R331W variant results in defects in neuronal differentiation. Considering glycolysis as a key regulatory mechanism of pluripotency and self-renewal, and its reduction in CTBP1R331W expressing cells, we are currently investigating the involvement of several upstream regulators that could link the defect in glycolysis with pluripotency, proliferation, cell fate determination, and differentiation. Thus, this study indicates that metabolic alteration contributes to the neurodevelopmental problems in HADDTS.