Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation

Abstract

Down syndrome (DS), a complex disorder that is caused by the trisomy of chromosome 21 (Hsa21), is a major cause of congenital heart defects (CHD). Interestingly, only about 50% of individuals with Hsa21 trisomy manifest CHD. Here we review the genetic basis of CHD in DS, focusing on genes that regulate extracellular matrix (ECM) organization. The overexpression of Hsa21 genes likely underlies the molecular mechanisms that contribute to CHD, even though the genes responsible for CHD could only be located in a critical region of Hsa21. A role in causing CHD has been attributed not only to protein-coding Hsa21 genes, but also to genes on other chromosomes, as well as miRNAs and lncRNAs. It is likely that the contribution of more than one gene is required, and that the overexpression of Hsa21 genes acts in combination with other genetic events, such as specific mutations or polymorphisms, amplifying their effect. Moreover, a key function in determining alterations in cardiac morphogenesis might be played by ECM. A large number of genes encoding ECM proteins are overexpressed in trisomic human fetal hearts, and many of them appear to be under the control of a Hsa21 gene, the RUNX1 transcription factor.

Characterization of the anterior segment in Trisomy 21-associated cataract using ultrasound biomicroscopy

“…Dysregulation of COLA6A1 and COLA6A2 genes, located on chromosome 21, leads to an increase in collagen type VI expression, which disrupts endocardial cushion differentiation during cardiac development [ 16 ]. Overexpression of type IV collagen increases the activity of extracellular matrix proteins and metalloproteinases, leading to increased adhesiveness of cells and a failure of embryonal endocardial cushion to septum fusion [ 17 ]. This results in the most common T21-associated cardiac anomaly, atrioventricular septal defect [ 18 ].…”

“…Abnormalities in extracellular matrix genes are known to be associated with cataract production and lens capsular rupture, suggesting a link between the development of congenital heart disease and early onset cataracts among T21 patients [ 19 ]. Overexpression of other genes on chromosome 21 also impairs mitochondrial function in fibroblasts of T21 cells, leading to an accumulation of reactive oxygen species, affecting cardiomyocyte differentiation, autophagy, and apoptosis [ 17 ]. In the anterior segment of the eye, oxidative stress and reactive oxygen species (ROS) are associated with cataract formation in the aging eye.…”

Congenital heart defects in Down syndrome are caused by increased dosage of DYRK1A

“…Adaptor trimming was performed with Trimmomatic/0.36-Java-1. 7 (61). Differential expression analysis was performed with the DESeq2 package within the R programming environment (62,63).…”

“…Several proteins encoded by Hsa21 genes have been proposed as candidates for the CHD. These include DSCAM and JAM2 adhesion molecules, COL6A1, COL6A2 and COL18A1 collagens, ADAMTS1 and ADAMTS5 metallopeptidases, the DYRK1A kinase, RCAN1, an inhibitor of calcineurin phosphatase, and SYNJ1, a regulator of endosomes ( 7 ). However, there has been no direct genetic demonstration of causality for any of these genes in studies that modulate gene dosage from 3 to 2 ( 2 ).…”

Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome

“…Several proteins encoded by Hsa21 genes have been proposed as candidates for CHD. These include DSCAM and JAM2 adhesion molecules; COL6A1, COL6A2, and COL18A1 collagens; ADAMTS1 and ADAMTS5 metallopeptidases; the DYRK1A (dual-specificity tyrosine phosphorylation–regulated kinase 1A) kinase; RCAN1, an inhibitor of calcineurin phosphatase; and SYNJ1, a regulator of endosomes ( 7 ). However, there has been no direct genetic demonstration of causality for any of these genes in studies that modulate gene dosage from 3 to 2 ( 2 ).…”