Causes of Clinical Diversity in Human TBX5 Mutations

Discovery of the many molecular signals that orchestrate cardiac development, a critical and complex embryologic process requiring integration of cell commitment,growth, looping, septation, and chamber specification,has predominantly come from studies in lower species.The study of human inherited cardiovascular malformations complements these investigations by providingabundant and unparalleled detail about the consequencesof cardiovascular development gone awry. Five percentof human live births and 10% of stillbirths have congenital heart disease (D'Alton and DeCherney 1993). Although the cause for these prevalent malformations isoften unknown, in rare instances cardiovascular malformations arise as a consequence of single gene mutations.Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by congenital heart defects and upperlimb anomalies is caused by mutations of TBX5, a member of the T-box gene family of transcription factors. Although a variety of different human TBX5 mutations havebeen identified located throughout the gene, most of theseare predicted to encode a truncated protein, thereby suggesting the predominant mechanism by which HOS occurs is haploinsufficiency of TBX5. Remarkably, the clinical phenotypes caused by TBX5 deficiency varyconsiderably, even in individuals with identical mutations, an observation that both alludes to the critical importance of TBX5 in many cardiovascular developmentalprocesses and indicates the influence of other factors inmodulating phenotype. Identification of the molecularbasis for HOS in concert with meticulous clinical evaluations that preface surgical intervention to correct humancongenital heart disease has provided the opportunity toassess the role of modifying genes and environment onthe molecular program of cardiac embryogenesis...