USING THE TS65DN MOUSE MODEL OF DOWN SYNDROME TO UNDERSTAND THE GENETICS OF CONGENITAL HEART DEFECTS

Down Syndrome;Congenital heart defects;Human Genetics and Molecular Biology

Polk, Renita C.Andrew, Deborah J. ;

Johns Hopkins University

关键词: Down Syndrome;    Congenital heart defects;    Human Genetics and Molecular Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/36959/POLK-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Down syndrome (DS) is the most common chromosomal abnormality in humans, caused by having three copies of human chromosome 21 (Hsa21). It is associated with a variety of features affecting almost every organ system, including the heart. There is an especially high incidence of congenital heart defect (CHD) in DS, where 40 – 50% of affected individuals have a CHD. CHD is the most common congenital defect in live births. The fact that half of those with DS have a normal heart suggests that additional genetic and environmental factors interact with trisomy 21 to cause CHD. Thus, people with trisomy 21 are sensitized to CHD.The Ts65Dn mouse model of DS was used as an analogous sensitized population to study the role of the Tbx5 gene in CHD. Tbx5 is a modifier of CHD known to play a role in chamber formation and septation of the heart. A Tbx5 null allele was introduced to Ts65Dn mice, and newborn pups were sacrificed and examined for CHDs. There is a significant difference between trisomic and euploid pups in the frequency of overriding aorta (OA). About 58% of the trisomic Tbx5+/- mice present with OA and a ventricular septal defect (VSD), while only 18% of the euploid pups have this defect. These results suggest that there is an interaction between Tbx5 and trisomy to increase the frequency of specific defects, and suggests a role for Tbx5 in development of the aorta. Results also suggest that the Tbx5 protein is involved in the transcriptional regulation of trisomic genes.The possibility of using the Ts65Dn mouse model to study the role of the Sonic hedgehog (Shh) pathway in CHD is also discussed here. Shh is known to be involved in heart development; Shh null mouse embryos exhibit a variety of heart defects. Ts65Dn mice showed a deficit in response to Shh in pharyngeal arches 1 and 2. If this deficit extends to all trisomic cells then it could contribute to CHD in trisomy. Pharyngeal arches 4 and 6 contribute to heart development and a Shh deficit in those regions would certainly contribute to heart defects. Trisomy is a destabilizing factor that, along with other modifiers, can cause a significant insult to heart development. These studies help in understanding the influence of those factors on heart development.