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Trisomy of human chromosome 21 (Hsa21) occurs in ~1 in 750 live births, and the resulting gene dosage imbalance gives rise to Down syndrome (DS). Around 45% of people with DS have a congenital heart defect but despite several decades of research, remarkably little progress has been made in identifying their cause.

A key obstacle has been the absence of an accurate animal model of DS that is amenable to experimental investigation. Without this, it is difficult to envisage progress towards identifying its underlying genetic causes or molecular mechanisms.

As part of a Wellcome Foundation-funded project, we are investigating the spectrum of heart malformations that occur in the Tc1 mouse (O'Doherty et. al., 2005), a transchromosomic line containing a freely segregating copy of almost the entire human chromosome 21.

3D models show AVSD in E14.5 (A,B) and E18.5 (C,D) Tc1 embryos, 4 chamber and long-axis views

Figure 1: 3D models show AVSD in E14.5 (A,B) and E18.5 (C,D) Tc1 embryos, 4 chamber and long-axis views. (arrowheads: ventricular septal defects; red arrows: bridging leaflets)

The "hallmark" cardiac abnormality in DS affects formation of the atrioventricular junction in the embryonic heart, frequently resulting in retention of a single, common junction between atria and ventricles, balanced between left and right sides and guarded by bridging valve leaflets. This atrioventricular septal defect (AVSD) results in shunting of blood between the two sides of the heart (usually at the atrial level) and requires surgical correction. Several trisomies of Mmu16 (the largest syntenic region with Hsa21) have already been produced, but none appear to provide an accurate mouse model of DS AVSD.

By taking advantage of the accuracy and rapid throughput possible with high resolution episcopic microscopy (HREM), we have been able to show that the transchromosomic Tc1 line accurately recapitulates the spectrum of DS cardiac abnormalities (Dunlevy et. al., 2010).

Defects range from balanced AVSD with single and separate valvar orifices, ventricular septal defects affecting membranous and muscular regions, anomalies of arterial trunk positioning and abnormal valve leaflet development.

Tc1 embryos exhibit endocardial cushion defects

Figure 2: Tc1 embryos exhibit endocardial cushion defects including cleft of the mitral valve (A), failure of the endocardial cushions to fuse (B). Arrowhead in B marks a VSD.

Ongoing studies are investigating the nature of the abnormalities in TC1 hearts at earlier stages of development in order to identify the affected tissues and cell populations. The Tc1 mouse model is an important tool to study the manner in which of gene dosage anomalies result in the production of heart defects during embryo development and by crossing the Tc1 mouse with individual gene knockouts, we are also examining the role individual genes may play in such malformations.

Collaborators - Victor Tybulewicz, the Crick - Elizabeth Fisher, Institute of Neurology, UCL