Molecular Pathogenesis of Down Syndrome (Trisomy 21)

Down syndrome is attributed to congenital chromosome 21. Its pathogenesis is driven by a range of cytopathic effects associated with aneuploidy, an area that has been the focus of extensive recent investigation.

Objective: To analyze and present, in the form of a narrative review, the molecular mechanisms underlying the detrimental effects of chromosome 21 on the cell. The first of these is a primary imbalance in gene expression caused by increased dosage of chromosome 21 genes and the hyperfunction of the encoded enzymatic, transport, receptor, structural, and regulatory proteins. In addition, the presence of an extra chromosome leads to secondary global dysregulation of gene expression driven by a range of cytopathic mechanisms, resulting in the development of an aneuploidy-associated phenotype. Among these mechanisms are features of proteotoxicity (stoichiometric imbalance; overload of the systems responsible for protein synthesis, folding, post-translational modifications, and degradation; inhibition of ribosomal biogenesis; and activation of integrated cellular stress response programs), disruption of the spatial organization of genetic material, and genome instability (in particular chromosomal instability), which is associated with the accumulation of errors in a wide range of genes and activation of autoinflammatory processes.

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