Abstract

Congenital heart diseases (CHD) are defects in the structure of the heart that are present at birth. They are amongst the most common birth defects and present in 9 out of 1000 births. Tetralogy of Fallot (ToF) is one of the most common CHD and is considered to be a multigenic condition as no single causative gene has been found so far. Studies on animal models have linked the development of TOF to defects in cardiac septation and heart valves formation. Our recent GWAS study found significant association of Tetralogy with Chr13q31 region (2 variants, p=7.4x10^-8) containing 2 poorly characterised genes, glypicans GPC5 and GPC6. Glypicans are transmembrane co-receptors involved in modulation of a number of signalling pathways. Available published data suggests that deletion of GPC5 has no effect on the embryonic development, while deletion of GPC6 may cause cardiac developmental abnormalities. We found that GPC6 is expressed exclusively in the mesenchymal cells (MC) populating endocardial cushions during critical stages of mouse and human cardiac septation, and later in the smooth muscle cells derived from these MC. We also found colocalisation of the Gpc6 with Pdgfra, suggesting novel GPC6 involvement in the regulation of Pdgf signalling pathway, required for cardiac septation, linking it to TOF defects.