Genetic analysis of Down syndrome-associated heart defects in mice

Abstract

Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Has21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we generated two novel mouse models carrying a 5.43-Mb duplication and a reciprocal deletion between Tiam1 and Kcnj6 using chromosome engineering, Dp(Tiam1-Kcnj6)Yey/+ and Df(Tiam1-Kcnj6)Yey/+, respectively, within the 22.9-Mb syntenic region on Mmu16. We found that Dp(Tiam1-Kcnj6)Yey/+, but not Dp(16)1Yey/Df(Tiam1-Kcnj6)Yey, resulted in heart defects, indicating that triplication of the Tiam1-Knj6 region is necessary and sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(Tiam1-Kcnj6)Yey/+ embryos confirmed elevated expression levels for the genes located in the Tiam-Kcnj6 region. Therefore, we established the smallest critical genomic region for DS-associated heart defects to lay the foundation for identifying the causative gene(s) for this phenotype.

Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity

“…A recent clinical investigation determined that the disorder of chromosome 21 monosomy also results in cardiac defects, including hypoplastic and hypertrophied left ventricle and atrial as well as ventricular septal defects (Fisher et al, 2013). Recent work in mice investigating congenital heart disease in individuals with DS exclude Chd5 from the minimal region that induces congenital heart disease upon duplication (Liu et al, 2011a). By contrast, a recent screen in zebrafish identified CHD5 as a regulator of myocardial repolarization (Milan et al, 2009), and subsequent work in the medaka fish demonstrated that CHD5-depleted hearts had general looping and chamber defects (Murata et al, 2009).…”

“…The diversity of cardiac phenotypes along with the inheritance of varying regions of an extra copy of chromosome 21, as well as additional chromosomal abnormalities in a subset of individuals with DS, has made identifying the crucial gene(s) for heart disease in DS patients problematic (Korbel et al, 2009;Lyle et al, 2009). Although recent studies have used mouse models to identify the putative crucial region in chromosome 21 that is associated with heart disease in DS patients, specific genes or groups of genes responsible for any of the cardiac phenotypes have not been identified (Shinohara et al, 2001;Liu et al, 2011a). Among the candidate genes is that encoding congenital heart disease protein 5 (CHD5), also known as tryptophan-rich basic protein (WRB).…”

Gender differences in the prevalence of congenital heart disease in Down’s syndrome: a brief meta-analysis

“…The reported prevalence of these defects varies among studies [8][9][10][11][12][13][14]. This could reflect inherent characteristics of the studied populations, such a higher frequency of genetic variances that predispose to the presence of AVSD [5,[15][16][17][18][19].…”

A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population

“…In our study, we noticed that the CBS −4673C>G could not show protective effects on non-isolated CHD cases (n = 315, P = 0.25) because the causative mutations for the complicated CHD are too strong to be reversed by the elevated CBS expression. Meanwhile, the triplicated Mmu17 mice, a Down syndrome model without CHD, indicated that the whole triplicated region covering 19 genes, including CBS, were excluded as the causative factor of Down syndrome CHD [36].…”