Congenital Heart Defects with GATA Transcription Factors

By: Ben DevenneyBiochemistry 2007

Basic Facts

• Congenital Heart Defects occurs in 5-8 out of every 1000 births- most common major birth defect

• 85% of those survive into adulthood• Approx 1 million adults in world today born

with some sort of CHD.• Heart is first organ to form in body.• Primarily Genetic

Various Forms of CHD

• Heart Murmur • Atrial Septal Defect• Coarctation of the Aorta• Ventricular Septal Defect• Aortic Stenosis• Cardiac Malpositions (ex- heart on right side)

CHD Testing

• Physical Appearance• X-Ray• Electrocardiogram• Echocardiogram• Palpation• Arterial Pulse

Causes of CHD

• Scientists still learning about heart formation and specific causes through Gene Targeting Experiments

• Occurs in error of instructions given to the developmental cells.

• GATA Family largely responsible for heart formation.

Animals used for Gene Targeting Experiments in studying the Human

Heart.

Heart Development

GATA Transcription Factors

• 6 GATA factors, but GATA -4 is primary one found to cause heart defects.

• GATA-4 regulates the second stage of cardiac development.

• GATA proteins are part of zinc finger transcription factor.

• Zinc Finger: a finger-shaped fold in a protein that permits it to interact with DNA and RNA. The fold is created by the binding of specific amino acids in the protein to a zinc atom.

GATA-4• Found on Chromosome 8p23.1-p22• Impairs ventricular growth• Necessary for sequence specific DNA binding activity• Procardiomyocytes fail to migrate from anterior to dorsal

region of the embryo to ventral midline to form linear heart tube.

• “Forced expression on GATA-4 in P19 cells accelerate cardiogenesis and increased the number of cardiac myocytes”

• On N-terminus of GATA-4, transcriptional activation domains identified (ADI and ADII)

• Both AD’s contain Tyrosine and Serine residues meaning posttranslational modifications of GATA-4