The App-Runx1 Region Is Critical for Birth Defects and Electrocardiographic Dysfunctions Observed in a Down Syndrome Mouse Model

Abstract

Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people.

Aortic dilation, genetic testing, and associated diagnoses

“…In this population some of the diagnoses included major aneuploidies that should be easily [6][7][8][18][19][20][21][22][23][24][25] In many cases, in spite of lacking further supporting clinical evidence of a direct link between AoD and the genes involved in the remaining patients with cytogenetic abnormalities, other potential candidate genes with relationships to cardiac morphogenesis or pathology were identified ( Table 3). [26][27][28][29][30][31][32][33][34][35] We also were able to identify other less common genetic conditions in this population. VACTERL association, which was the most common, has been associated with a variety of heart defects, including BAV and conotruncal defects, but was not typically been associated with AoD in large series of patients.…”

Cognition and Hippocampal Plasticity in the Mouse Is Altered by Monosomy of a Genomic Region Implicated in Down Syndrome

“…All methods from RNA extraction to cDNA quantification have been already described in previous work (Lopes Pereira et al 2009; Raveau et al 2012). We focused on the Abcg1–U2af1 genes plus genes located at the borders and a few genes among Mmu10 and -16 homologous regions.…”

Mouse-based genetic modeling and analysis of Down syndrome

“…It is estimated that for every~39 kb of the genome at least one targeting vector is available for endpoint targeting. 30 The [31][32][33] will result in Cre/loxP-mediated transrecombination in the compound mutants and lead to Dp and Df in the progeny. Using these procedures, several laboratories have generated a substantial number of chromosomal rearrangements in Hsa21 syntenic regions in mice (Figs 3 and 4).…”

“…[34][35][36][37][38] To determine if a given relatively small region is necessary for a phenotype, a subtractive strategy can be used by compounding a larger duplication with a deletion of the smaller sub-region. 33,[39][40][41][42] Using different combinations of Dp and Df mutants, the smallest genomic region can be identified for a specific DS phenotype. If this region contains 10 or more Hsa21 gene orthologs, it might be necessary to generate new Dp and/or Df mutants to further dissect the region.…”

“…36,72 Besides developmental cognitive deficits, other phenotypes of DS that have also been analyzed in new models include heart defects, 33,[73][74][75] Another key phenotype in DS is AD, which is early onset with AD-type neurodegeneration detected by age 40 for all the individuals carrying Ts21. 78 The neuropathological findings of AD in DS are very similar to AD without Ts21 in the pattern of emergence of specific pathological markers, which include neuritic plaques and neurofibrillary tangles.…”