Guest post by Bum-Jun Kim (ASHG talk: Wednesday, 4:30pm – 4:45pm in Room 6D)
1p36 deletion syndrome is a genetic disorder caused by deletion of specific regions in p arm of chromosome 1 (1p36). Deletion of chromosome 1p36 is one of the most common terminal deletions in humans and found in children with incidence of 1 in 5,000 newborns. People carrying terminal or interstitial deletions have problems in the heart, the brain, growth, vision, and intelligence. A few genes are suggested as a causative gene for defects seen in 1p36 deletion syndrome due to wide range of deletion length. We have unveiled that RERE is one of the causative genes for symptoms seen in these individuals by using the mouse models (RERE-deficient mice) in which function of RERE is limited. RERE-deficient mice show similar defects developed in 1p36 deletion syndrome. We also described that individuals with single mutations in RERE gene present many of defects seen in 1p36 deletion syndrome.
Congenital heart defect is seen in approximately 70% of individuals with 1p36 deletions, with 23% having ventricular septal defects (VSDs), and 28% having atrial septal defects (ASDs). We have described that RERE-deficient mice also show VSDs with other congenital heart defects. In order to understand how RERE deficiency develops VSDs, we investigated RERE-deficient mice and heart specific RERE-deficient mice in which Rere is ablated from the heart by Tie2 Cre. In wild type mice, the atrioventricular cushions (AVCs) are filled with mesenchymal cells produced by epithelial-to-mesenchymal transition (EMT) and contribute to complete development of ventricular septum. However, RERE-deficient mice show decreased number of mesenchymal cells and abnormal EMT in the AVCs, which leads VSDs. Heart specific RERE deficiency also results in same defects seen in the heart of RERE-deficient mice. A gene called, Gata4 is known to be important for development of the heart and ablation of GATA4 in the heart causes similar phenotypes developed in the heart of RERE-deficient mice. Expression of Gata4 is reduced in the heart of RERE-deficient mice. In addition, we demonstrated that RERE regulates transcriptional activity of Gata4 promoter in vitro systems. The main finding of this study is that RERE-deficiency leads to decrease of GATA4 expression and development of VSDs with abnormal EMT.
Our research is currently published in Disease Models & Mechanisms 2018