The roles of the T -box transcription factor genes TBX3 and TBX5 in limb and cardiac development

The following thesis defines some of the roles of the T-box transcription factor genes TBX3 and TBX5 in limb and heart development through the study of naturally occurring human mutations. From detailed genetic analysis of affected patients with Holt-Oram syndrome and ulnar-mammary syndrome, we have been able to assemble a framework of a few of the functions of these genes in the developmental process. The critical points of this thesis originate from the dual findings that mutations in TBX5 cause Holt-Oram syndrome and mutations in TBX3 cause ulnar-mammary syndrome. The regulation of these transcription factors is so delicately balanced that haploinsufficiency of either gene product can cause severe phenotypes. Genotype/phenotype analyses of TBX5 mutations indicate that TBX5 interacts differently with DNA targets in distinct organ systems. Alternative splicing of TBX3 in the T-box domain results in an isoform of TBX3 that binds to DNA more tightly or dimerizes more efficiently. Identification of some of the functions of these genes offers a springboard from which future studies about T-box genes and their roles in these developmental pathways can be launched.