CSL Protein Point Mutations Associated with Adams-Oliver Syndrome Show Reduced DNA Binding Affinity
Start Date
April 2025
Location
3rd floor - Library
Abstract
Adams-Oliver Syndrome (AOS) is a rare multiple-malformation human genetic disorder which is characterized by scalp, cranium, and transverse limb developmental defects. Several point mutations within the CSL transcription factor protein of the Notch signaling pathway have been associated with AOS. CSL can bind DNA and transcriptional corepressor/coactivator proteins. "); border-bottom: 1px solid transparent; background-size: 5px; vertical-align: 0.0178773px; line-height: 0px; position: relative;">Six point mutations in CSL have been identified in patients with AOS. In the mouse CSL protein sequence, these mutations correspond to residues Y86C, E89G, R91G, F92V, K195E, and S358R. We purified each of these CSL variants and performed thermal shift assays and isothermal titration calorimetry (ITC). Our results indicate that each CSL variant was properly folded but specifically showed reduced binding to DNA. While DNA binding affinity was reduced, these mutations had no effect on CSL binding affinity to corepressors or coactivators. These findings agree with a newly established mouse model of AOS that is currently under review which indicates that these CSL variants cause a dominant negative Notch phenotype (Solano et al. Manuscript in preparation).
CSL Protein Point Mutations Associated with Adams-Oliver Syndrome Show Reduced DNA Binding Affinity
3rd floor - Library
Adams-Oliver Syndrome (AOS) is a rare multiple-malformation human genetic disorder which is characterized by scalp, cranium, and transverse limb developmental defects. Several point mutations within the CSL transcription factor protein of the Notch signaling pathway have been associated with AOS. CSL can bind DNA and transcriptional corepressor/coactivator proteins. "); border-bottom: 1px solid transparent; background-size: 5px; vertical-align: 0.0178773px; line-height: 0px; position: relative;">Six point mutations in CSL have been identified in patients with AOS. In the mouse CSL protein sequence, these mutations correspond to residues Y86C, E89G, R91G, F92V, K195E, and S358R. We purified each of these CSL variants and performed thermal shift assays and isothermal titration calorimetry (ITC). Our results indicate that each CSL variant was properly folded but specifically showed reduced binding to DNA. While DNA binding affinity was reduced, these mutations had no effect on CSL binding affinity to corepressors or coactivators. These findings agree with a newly established mouse model of AOS that is currently under review which indicates that these CSL variants cause a dominant negative Notch phenotype (Solano et al. Manuscript in preparation).
