Using gene-editing to understand two mutations that cause congenital heart disease

Investigating the role of Dock6 and EOGT in cardiac development and congenital heart disease (Ms Emma Armitage)

People with Adams-Oliver syndrome (AOS) are often born with congenital heart defects, which are abnormalities in the heart structure. Recent studies found that two mutations - or faults - in molecules called Dock6 and EOGT can cause AOS, but the exact way these mutations affect heart development is not yet known. Dock6 and EOGT normally control the activity of two other molecules, Rac1 and Notch, which are both very important in normal heart development. This study will use sophisticated gene-editing techniques in zebrafish to either remove the Dock6 and EOGT genes, or make very specific gene mutations similar to those found in people with AOS. They will then use state-of-the-art microscopes to analyse different aspects of heart development in the mutant zebrafish. Studying heart formation in zebrafish entirely missing the Dock6 and EOGT genes will reveal which stages and components of heart development these molecules are required for in normal heart development. In zebrafish with the AOS-like mutations, they could learn how this normal process of development goes wrong in people with AOS. Not only will this project reveal crucial insights into congenital heart defects that affect around 1% of all births, it will generate a zebrafish model of AOS that could help other researchers better understand how congenital heart defects form in people with AOS.