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.
Highlights
Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21; Hsa for Homo sapiens) is the most common chromosomal anomaly and cause of intellectual disabilities [1,2,3,4]
Among 617 mice born from Ts65Dn x B6C3B crosses, 34% Ts65Dn individuals were observed at weaning (Table 1), far below the 50% that could be expected (x2 P = 1.7461028)
Heart and great vessels microdissection and cardiac histology analyses showed one out of 18 Ts65Dn dead pups presenting both great vessel and cardiac malformations (Figure 1). In this Ts65Dn pup, the right subclavian artery arose from the distal part of the aortic arch downstream the left subclavian artery connection and described a retro-oesophagian loop instead of arising from the proximal part of the aortic arch forming a common trunk with the right carotid artery
Summary
Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa; Hsa for Homo sapiens) is the most common chromosomal anomaly and cause of intellectual disabilities [1,2,3,4]. Among DS newborns, 40% to 60% are affected by congenital heart defects (CHD), consisting mainly of atrioventricular septal defects (AVSD) with additional changes in the cardiac axis and ECG [5,6]. Thanks to cardiac surgery and medical care, CHD patient’s life expectancy has increased from 12 years in the 1940s to 60 years nowadays [1,5]. Even in the absence of overt CHD, a number of functional anomalies have been observed in adult DS patients, such as altered heart rate regulation [7,8], valvular dysfunction [9,10], bradycardia and AV block [11,12]. Adult DS population has increased and requires prolonged follow up and care, in the cardiovascular field
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