To identify novel genes that regulate cardiac differentiation and morphogenesis, we have applied molecular genetic techniques to a number of congenital and inherited disorders of human cardiac growth and development. Major projects include the following investigative programs:

1. Congenital cardiac and upper limb malformations characterize the autosomal dominant disorder Holt-Oram syndrome. Our genetic analyses mapped the Holt-Oram gene to human chromosome 12q24.1 and identified TBX5, a human T-box transcription factor. Sequence analyses demonstrated a variety of mutations in this gene which cause Holt-Oram syndrome. Correlation of TBX5 genotypes with Holt-Oram phenotypes suggests that TBX5 mutations produce a combination of severe limb and severe cardiac malformation through both haploinsufficiency and steric hindrance at DNA binding sites. Retroviral overexpression in vitro studies and in vivo studies in the embryonic chick heart demonstrate that TBX5 acts as cellular growth arrest signal. Ongoing experiments are exploring the effects of mutant and wildtype TBX5 on myocardial, epicardial, endocardial, and vascular differentiation and morphogenesis.

2. Intracardiac tumors, including atrial myxomas, are significant causes of stroke and heart failure and may present as heritable systemic disorders. Carney complex is an autosomal dominant syndrome in which intracardiac myxomas arise in the setting of cutaneous hyperpigmentation and endocrinopathy. We initially defined a novel chromosome 17q2 locus that contains the Carney complex disease gene in several families. Our further positional cloning studies have now identified mutations in the gene encoding the R1alpha regulatory subunit of cAMP-dependent protein kinase A that cause intracardiac myxomas and this disorder. Ongoing studies are currently exploring the consequences of these gene mutations on cardiac growth and development in vitro and in vivo in the chick and mouse. Recently we have discovered that some forms of cardiac tumors are associated with limb deformity and are due to mutations in an unusual perinatal form of myosin. We are currently exploring how perinatal myosin defects lead to limb contractures and to cardiac tumors.

3. Aortic aneurysms and dissections are important causes of human morbidity and mortality. Approximately 20% result from heritable disorders. We have investigated autosomal dominant forms of aortic aneurysm disease that are genetically and phenotypically distinct from Marfan and Ehlers-Danlos syndromes. Recent linkage analyses have defined a novel 2 cM chromosomal locus containing a gene defect that causes such a mendelian form of aortic disease. Ongoing positional cloning studies seek to identify the specific mutated gene at this locus.


Email: ctbasson@med.cornell.edu