Mental retardation in Down syndrome: From gene dosage imbalance to molecular and cellular mechanisms

Down syndrome (DS), the most frequent genetic disorder leading to mental retardation (MR), is caused by three copies of human chromosome 21 (HC21). Trisomic and transgenic mouse models for DS allow genetic dissection of DS neurological and cognitive disorders in view to identify genes responsible for these phenotypes. The effects of the gene dosage imbalance on DS phenotypes are explained by two hypotheses: the “gene dosage effect” hypothesis claims that a DS critical region, containing a subset of dosage-sensitive genes, determines DS phenotypes, and the “amplified developmental instability” hypothesis holds that HC21 trisomy determines general alteration in developmental homeostasis. Transcriptome and expression studies showed different up- or down-expression levels of genes located on HC21 and the other disomic chromosomes. HC21 genes, characterized by their overexpression in brain regions affected in DS patients and by their contribution to neurological and cognitive defects when overexpressed in mouse models, are proposed herein as good candidates for MR. In this article, we propose a new molecular and cellular mechanism explaining MR pathogenesis in DS. In this model, gene dosage imbalance effects on transcriptional variations are described considering the nature of gene products and their functional relationships. These transcriptional variations may affect different aspects of neuronal differentiation and metabolism and finally, determine the brain neuropathologies and mental retardation in DS.