Abstract
Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype–phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 16 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted six biological cascades centred around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene–gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.
Highlights
Down syndrome (DS) is the most common genetic form of intellectual disability and was first described as a disease by John Langdon Down in 1866
We wanted to dissect the contribution of sub-regions located in the telomeric part of M. musculus chromosome 16 (Mmu16), homologous to Hsa21 [36], to DS-related cognitive phenotypes
We found no changes in the expression of RHOA, converging with the transcriptomic analyses, but we detected a significant decrease of myosin light chain (MLC) phosphorylation (P-MLC) in the Dp1Yey hippocampi compared with control (Supplementary Material, Fig. S16)
Summary
Down syndrome (DS) is the most common genetic form of intellectual disability and was first described as a disease by John Langdon Down in 1866. In rare cases, people with partial Hsa duplications have been observed with a smaller spectrum of DS features Studying these rare conditions increased our understanding of the genotype–phenotype correlations in DS [4,5,6,7,8,9,10]: there is no single trisomic region responsible for all DS features, rather there are several susceptibility regions when presented in three copies that contributes to DS features in people with partial duplication of Hsa. Studying these rare conditions increased our understanding of the genotype–phenotype correlations in DS [4,5,6,7,8,9,10]: there is no single trisomic region responsible for all DS features, rather there are several susceptibility regions when presented in three copies that contributes to DS features in people with partial duplication of Hsa21 This can induce a Received: October 30, 2020.
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