The successes of cloning genes causative for human genetic disorders have immediate benefits for affected individuals through the ability to offer molecular genetic testing. The long-term-benefits will emerge from the characterization of the gene products. The characterization of these products is especially important for genes for which no function can immediately be assigned. Such a situation exists for Treacher Collins syndrome (TCOF 1), an autosomal dominant disorder of craniofacial development. The facial structures affected in TCOF 1 include the lower jaw, cheekbones, the middle and external ears and the secondary palate. The TCOF1 gene has been identified but the function of the gene product, treacle, in normal development is not known. TCOF1 is related to a class of nucleolar phosphoproteins that appear to have dual functions. It is known that these proteins are important in ribosome assembly and transport and one of these proteins, Nopp 140, is also a stage-specific transcription factor. The mechanism by which a protein that affects a general function of cells such as ribosome assembly could cause a specific developmental disease is unclear. If treacle, like Nopp 140, has more than one function and can act as a developmental stage-specific transcription factor, then the phenotype of the disease is more readily explained. The research objectives of this study are to determine the function of the TCOF 1 protein product treacle by 1) elucidating the basic biochemical properties of the protein including identifying proteins that can directly interact with treacle; 2) describing the developmental distribution of the TCOF 1 transcript and protein product; 3) using a mouse model to determine the specific developmental defect of the disorder and to determine if the expression of other genes downstream to the defect are changed and; 4) to determine the mechanisms by which mutations in the TCOF1 gene cause their effects. It will be interesting to ascertain how a gene that appears to have a very general effect or is a member of a family of ubiquitously expressed genes can have a tissue and developmentally specific phenotype. This study will not only be important in understanding TCOF1 but also aid in elucidating one pathway underlying craniofacial development.
| Shows, Kathryn H; Shiang, Rita (2008) Regulation of the mouse Treacher Collins syndrome homolog (Tcof1) promoter through differential repression of constitutive expression. DNA Cell Biol 27:589-600 |
| Shows, Kathryn H; Ward, Christy; Summers, Laura et al. (2006) Reduced TCOF1 mRNA level in a rhesus macaque with Treacher Collins-like syndrome: further evidence for haploinsufficiency of treacle as the cause of disease. Mamm Genome 17:168-77 |
| Mogass, Michael; York, Timothy P; Li, Lin et al. (2004) Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma. Biochem Biophys Res Commun 325:124-32 |
