Holt-Oram syndrome is an autosomal dominant condition characterized by congenital cardiac defects and forelimb anomalies. Clinical manifestations of Holt-Oram syndrome can vary over a wide range. Since the molecular basis for this clinical variability is unknown, managing and counseling patients and famililies can become problematic. Recently mutation of TBX5 was demonstrated to cause Holt-Oram syndrome. TBX5 is a member of the T-box gene family and probably encodes a transcription factor that regulates the expression of other gene(s) involved in cardiac and limb development. To understand the molecular basis of the clinical phenotype of the disease, we have looked for mutations in patients with Holt-Oram and evaluated clinical phenotype for those with mutation in the TBX5 gene. Clinical data were correlated to the class of the mutations. Correlative clinical phenotype-genotype analysis suggest that congenital malformations were more severe in individuals with mutations resulting in truncation of the TBX5 protein than in those with missense mutations. Results suggest that there are distinct physiologic consequences of TBX5 defects in limb and heart development. Further studies are necessary. The goals of this research project are: 1) to further elucidate the genotype-phenotype correlation; 2) to isolate and characterize the promoter of TBX5; 3) to provide insights into the understanding of the structure-function relationship of TBX5; 4) to define the full clinical spectrum of Holt-Oram syndrome; 5) to provide guidance for the future clinical laboratory testing of Holt-Oram syndrome. The information gained should shed light on the molecular basis of more common congenital heart diseases and limb malformations.
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