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Title: The role of T-box transcription factor TBX22 in craniofacial development
Author: Andreou, Artemisia Maria
ISNI:       0000 0004 2671 5944
Awarding Body: Imperial College London (University of London)
Current Institution: Imperial College London
Date of Award: 2007
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X-linked cleft palate and ankyloglossia (CPX) is a semi-dominant condition caused by mutations in the T-box transcription factor gene TBX22, which accounts for around 5% of all cleft palate patients. TBX22 is expressed in the developing palatal shelves and tongue in both human and mouse embryos, however, biochemical function of the protein and its precise role in the cleft palate phenotype are still lacking. Various types of mutations have been identified in CPX patients, but notably most of the missense mutations localize within the DNA-binding T-box domain. This project set out to investigate the effects of naturally occurring missense mutations on protein function. Full-length wild type and mutant proteins were expressed in vitro and compared for DNA binding ability, localization to the nucleus and transcriptional activity. Protein trafficking into the nucleus was unaffected for all ten mutants tested. Both DNA-binding and transcriptional repression was abolished or considerably compromised for many of the mutants compared to wild-type although some were more mildly affected, perhaps reflecting their role in protein-DNA or protein-protein interaction. Many transcriptional repressors are subject to post-translational modification by the small ubiquitin-related modifier SUMO. In silico analysis of TBX22 shows that it contains several consensus SUMOylation sequences. Direct interaction between the two proteins was demonstrated both by western blotting and co-immunoprecipitation studies. Treatment with SUMO-specific proteases or mutation of the SUMO attachment sites show that SUMOylation is required for transcriptional repression. Cell based analysis of the CPX missense mutants showed that they uniformly fail to be modified by endogenous SUMO, suggesting involvement of a common mechanism. Collectively, the data suggests that the CPX phenotype results from loss of TBX22 repressor activity and that SUMO conjugation is likely to be a key factor during normal craniofacial development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available