Interferon hyperactivity impairs cardiogenesis in Down syndrome via downregulation of canonical Wnt signaling
Intensive effort has been focused on identifying chromosomal regions of HSA21 responsible for CHDs. HSA21 is homologous to portions of at least three murine chromosomes: MMU16, MMU17, and MMU10 and various mouse models of DS have been created with triplication of these regions and smaller subregions. Trisomy for MMU10 or MMU17 does not cause CHDs in these mouse models. However, ∼50% of mice with trisomy of MMU16, such as Dp(16)1Yey/+ (hereafter referred to as Dp16), display CHDs, resembling cardiac defects in people with DS. Using mouse strains with trisomy of MMU16, Liu et al. suggested a 3.7 Mb genomic region from Tiam1 to Kcnj6 was sufficient to cause heart defects in mice. This 3.7 Mb genomic region contains a cluster of four interferon (IFN) receptor (IFNR) genes: Ifnar, Ifnar2, Ifngr2, and Il10rb. In addition, genetic variants in human IFNGR2 and IL10RB have been associated with CHDs in DS from two cohort studies composed of 198 individuals and 702 individuals, respectively. In the Dp16 mouse model, we recently showed that normalization of copy number of the Ifnr cluster prevented heart malformations, but the mechanisms by which hyperactive IFN signaling may disrupt normal heart development await elucidation.