Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse

Dunlevy, Louisa P. E.; Bennett, M. W.; Slender, Amy; Lana-Elola, Eva; Tybulewicz, Victor L. J.; Fisher, Elizabeth; Mohun, Timothy J.

doi:10.1093/cvr/cvq193

Cited by 52 publications

(52 citation statements)

References 44 publications

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“…We and the others have shown that the triplication of the Cbr1-Fam3b does not cause heart defects in the Ts1Rhr embryos (Fig. 1) (Dunlevy et al 2010; Liu et al 2011b). Because of the presence of a 1.6-Mb overlapping duplicated region between Dp(16)4Yey and Ts1Rhr, which carries 14 Hsa21 gene orthologs (Fig.…”

Section: Discussionmentioning

confidence: 59%

Engineered chromosome-based genetic mapping establishes a 3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice

et al. 2013

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Trisomy 21 (Down syndrome, DS) is the most common human genetic anomaly associated with heart defects. Based on evolutionary conservation, DS-associated heart defects have been modeled in mice. By generating and analyzing mouse mutants carrying different genomic rearrangements in human chromosome 21 (Hsa21) syntenic regions, we found the triplication of the Tiam1-Kcnj6 region on mouse chromosome 16 (Mmu16) resulted in DS-related cardiovascular abnormalities. In this study, we developed two tandem duplications spanning the Tiam1-Kcnj6 genomic region on Mmu16 using recombinase-mediated genome engineering, Dp(16)3Yey and Dp(16)4Yey, spanning the 2.1Mb Tiam1-Il10rb and 3.7Mb Ifnar1-Kcnj6 regions, respectively. We found that Dp(16)4Yey/+, but not Dp(16)3Yey/+, led to heart defects, suggesting the triplication of the Ifnar1-Kcnj6 region is sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(16)4Yey/+ embryos showed that the Hsa21 gene orthologs located within the duplicated interval were expressed at the elevated levels, reflecting the consequences of the gene dosage alterations. Therefore, we have identified a 3.7Mb genomic region, the smallest critical genomic region, for DS-associated heart defects, and our results should set the stage for the final step to establish the identities of the causal gene(s), whose elevated expression(s) directly underlie this major DS phenotype.

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Section: Discussionmentioning

confidence: 59%

Engineered chromosome-based genetic mapping establishes a 3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice

et al. 2013

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“…Studies investigating the penetrance and variability in DS phenotypes have previously singled out nontrisomic genes as important factors in DS phenotypes (Epstein 2001;Kerstann et al 2004). For example, nontrisomic CRELD1 mutations have been linked to an increased penetrance of atrioventricular septal defects in individuals with DS, and the occurrence of DS-like heart defects in the Tc1 DS mouse model were dependent upon genetic background (Maslen et al 2006;Dunlevy et al 2010). Certain alleles of GATA1, also not found on Hsa21, may predispose individuals with Ts21 to DS-related acute megakaryoblastic leukemia (Wechsler et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Trisomic and Allelic Differences Influence Phenotypic Variability During Development of Down Syndrome Mice

Deitz

Roper

2011

Genetics

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Individuals with full or partial Trisomy 21 (Ts21) present with clinical features collectively referred to as Down syndrome (DS), although DS phenotypes vary in incidence and severity between individuals. Differing genetic and phenotypic content in individuals with DS as well as mouse models of DS facilitate the understanding of the correlation between specific genes and phenotypes associated with Ts21. The Ts1Rhr mouse model is trisomic for 33 genes (the "Down syndrome critical region" or DSCR) hypothesized to be responsible for many clinical DS features, including craniofacial dysmorphology with a small mandible. Experiments with Ts1Rhr mice showed that the DSCR was not sufficient to cause all DS phenotypes by identifying uncharacteristic craniofacial abnormalities not found in individuals with DS or other DS mouse models. We hypothesized that the origins of the larger, dysmorphic mandible observed in adult Ts1Rhr mice develop from larger embryonic craniofacial precursors. Because of phenotypic variability seen in subsequent studies with Ts1Rhr mice, we also hypothesized that genetic background differences would alter Ts1Rhr developmental phenotypes. Using Ts1Rhr offspring from two genetic backgrounds, we found differences in mandibular precursor volume as well as total embryonic volume and postnatal body size of Ts1Rhr and nontrisomic littermates. Additionally, we observed increased relative expression of Dyrk1a and differential expression of Ets2 on the basis of the genetic background in the Ts1Rhr mandibular precursor. Our results suggest that trisomic gene content and allelic differences in trisomic or nontrisomic genes influence variability in gene expression and developmental phenotypes associated with DS.

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“…Recent studies also suggest the potential contribution of VEGFA (Ackerman et al 2012), ciliome and Hedgehog (Ripoll et al 2012), and folate (Locke et al 2010) pathways to the pathogenicity of CHD in DS. There are also several mouse models for partial or complete trisomy syntenic to human chromosome 21 (Sago et al 1998;Shinohara et al 2001;Dunlevy et al 2010;Yu et al 2010). CHDs have been observed in the full ''trisomy 21'' homologous mice Tc1 (Dunlevy et al 2010) and Dp(10)1Yey/+; Dp(16)1Yey/+; Dp(17)1Yey/+ mice (Yu et al 2010).…”

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confidence: 99%

“…There are also several mouse models for partial or complete trisomy syntenic to human chromosome 21 (Sago et al 1998;Shinohara et al 2001;Dunlevy et al 2010;Yu et al 2010). CHDs have been observed in the full ''trisomy 21'' homologous mice Tc1 (Dunlevy et al 2010) and Dp(10)1Yey/+; Dp(16)1Yey/+; Dp(17)1Yey/+ mice (Yu et al 2010). In addition, CHDs have been observed in the partial ''trisomy 21'' model Ts65Dn that is trisomic for 13.4 Mb of the 22.9-Mb chromosome 21 syntenic regions (Moore 2006;Williams et al 2008).…”

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confidence: 99%

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

et al. 2013

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Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21-specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR £ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS-without CHD (FDR £ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295 ) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yetunidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.

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Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse

Cited by 52 publications

References 44 publications

Engineered chromosome-based genetic mapping establishes a 3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice

Engineered chromosome-based genetic mapping establishes a 3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice

Trisomic and Allelic Differences Influence Phenotypic Variability During Development of Down Syndrome Mice

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

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