Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel

Abstract

Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes that cause DS phenotypes, including CHD, we used chromosome engineering to generate a mapping panel of 7 mouse strains with partial trisomies of regions of mouse chromosome 16 orthologous to Hsa21. Using high-resolution episcopic microscopy and three-dimensional modeling we show that these strains accurately model DS CHD. Systematic analysis of the 7 strains identified a minimal critical region sufficient to cause CHD when present in 3 copies, and showed that it contained at least two dosage-sensitive loci. Furthermore, two of these new strains model a specific subtype of atrio-ventricular septal defects with exclusive ventricular shunting and demonstrate that, contrary to current hypotheses, these CHD are not due to failure in formation of the dorsal mesenchymal protrusion.DOI: http://dx.doi.org/10.7554/eLife.11614.001

New approaches to studying early brain development in Down syndrome

“…This has led to the development of the most complete ‘triple trisomic mouse’ which develops Down syndrome‐related neurological impairments . The Dp1Tyb and Dp16 contain the largest duplication of Mmu16, carrying an extra copy of 148 genes which is the entire region of Mmu16 that is orthologous to Hsa21 and does not perturb genes on any other chromosomes . Whilst the triple trisomic mouse is incredibly labour intensive and costly to produce, assessing each individual trisomic mouse is providing further insight into the contribution of gene imbalance to Down syndrome phenotype.…”

What people with Down Syndrome can teach us about cardiopulmonary disease

“…The most recent data suggest that many Hsa21 (i.e. dosage-sensitive) genes are required for development of CHD, but that no single gene may be required [131,132].…”

Perinatal Natural History of the Ts1Cje Mouse Model of Down Syndrome: Growth Restriction, Early Mortality, Heart Defects, and Delayed Development

“…Cardiac malformations have also been observed in Dp(16)1Yey E18.5 embryos, including VSD, ASD, cleft mitral valves, severe coarctation of the aorta, double outlet right ventricle (DORV) and tetralogy of Fallot (TOF) [5]. In a recent study, Lana-Elola et al (2016) generated seven different mouse strains that carry different segmental trisomies of Hsa21 orthologous genes (including the Dp(16)Tyb1 mouse model equivalent to the Dp(16)1Yey model) to identify candidate genes or regions that are responsible for heart defects in DS [30]. They examined embryos at E14.5 using high-resolution episcopic microscopy (HREM) and found that 61.5% of the Dp1Tyb (carrying a duplication of 148 genes between Lipi - Zbtb21 similar to the Dp16 mice) and 44% in the Dp3Tyb (carrying a duplication of 40 genes between Mir802 - Zbtb21 ) present with heart defects, including AVSD, VSD and ASD.…”

“…They examined embryos at E14.5 using high-resolution episcopic microscopy (HREM) and found that 61.5% of the Dp1Tyb (carrying a duplication of 148 genes between Lipi - Zbtb21 similar to the Dp16 mice) and 44% in the Dp3Tyb (carrying a duplication of 40 genes between Mir802 - Zbtb21 ) present with heart defects, including AVSD, VSD and ASD. These authors, however, also identified a high incidence of heart defects in WT littermates from these two new strains (27% and 12% of WT in the Dp1Tyb and Dp3Tyb strains, respectively) [30]. …”